Study of Testosterone and Recombinant Human Growth Hormone in Facioscapulohumeral Muscular Dystrophy

Abstract

Background and Objectives

Effective therapies for facioscapulohumeral muscular dystrophy (FSHD) are currently limited. Recombinant human growth hormone (rHGH) combined with testosterone (combination therapy) may have meaningful clinical effects on ambulation, strength, muscle mass, and disease burden. As such, combination therapy has the potential to limit disease progression and functional decline in individuals with muscular dystrophy. The objective of this study was to evaluate the safety, tolerability, and potential efficacy of combination therapy in adult men with FSHD.

Methods

This investigator-initiated, single-center (University of Rochester), single-arm, proof-of-concept study evaluated the safety and tolerability of combination therapy in ambulatory adult men with FSHD. Participants received daily rHGH combined with testosterone enanthate injections every 2 weeks for 24 weeks, followed by a 12-week washout period. Participants underwent serial safety and laboratory assessments to monitor safety and tolerability during the study. Participants were also evaluated for changes from baseline in lean body mass (LBM) and fat mass, measured by dual-energy X-ray absorptiometry; ambulation, measured by 6-minute walk distance; strength; clinical function, measured using the FSHD-Composite Outcome Measure (FSHD-COM); and patient-reported disease burden, measured by the FSHD Health Index (FSHD-HI).

Results

Nineteen of 20 participants completed the study, with no participants experiencing a serious adverse event. The most common adverse event was mild injection site reaction at the rHGH and/or testosterone injection site. After 24 weeks, LBM improved by 2.21 kilograms (95% CI 1.35–3.07; p < 0.0001), fat mass decreased by 1.30 kilograms (95% CI −2.56 to −0.04; p = 0.04), 6-minute walk distance increased by 37.3 m (95% CI 18.3–56.9; p = 0.001), overall strength (average % of predicted normal) increased by 3% (95% CI 0.3–5.6; p = 0.03), clinical function (FSHD-COM) improved by 2.4 points (95% CI 4.0–0.8; p = 0.006), and total disease burden (FSHD-HI) decreased by 6.1 points (95% CI −12.0 to −0.2; p = 0.04).

Discussion

Combination therapy was safe and well tolerated in men with FSHD. Participants experienced improvements in ambulation, strength, muscle mass, and disease burden after receiving this study intervention. Larger randomized, double-blind, placebo-controlled trials are needed to further investigate this promising therapeutic approach.

Trial Registration Information

Registered on ClinicalTrials.gov: NCT03123913.

Introduction

Facioscapulohumeral muscular dystrophy (FSHD) is the second most common form of adult-onset muscular dystrophy in the world.^1,2 Clinically, FSHD is characterized by progressive weakness and atrophy of the face, shoulders, arms, and hip girdle muscles; impaired ambulation; and functional impairment related to muscle weakness. In a study characterizing the functional impairment of individuals with FSHD in a national registry, participants had a 24% chance of losing ambulation over a 6-year interval.³ In another study documenting changes in disease burden over time, participants with FSHD demonstrated reductions in their strength over 12 months.⁴ Currently, there are no approved therapies that effectively treat weakness, muscle atrophy, or functional decline in FSHD.

Testosterone is a naturally occurring androgen that is produced in both men and women. Testosterone promotes protein synthesis and has anabolic effects on both muscle and bone.⁵ It is indicated and prescribed for men with hypogonadism and conditions associated with low or no endogenous testosterone.⁶ Human growth hormone (HGH) is a naturally occurring peptide hormone that is produced in the pituitary gland of men and women. Like testosterone, HGH can stimulate cell growth and regeneration.⁷ In a study of an HGH-deficient state, participants experienced exercise intolerance, low bone mineral density, changes in body composition, and a worsening cholesterol profile.⁸ Recombinant HGH (rHGH) is a synthesized preparation of HGH that has been used to treat children and adults with growth hormone deficiency as well as those with muscle wasting, Turner syndrome, Prader-Willi syndrome, chronic renal failure, and idiopathic short stature.^7,9-15

Prior research has led to the scientific premise that combination therapy (testosterone combined with rHGH) is safe and potentially effective in increasing strength, respiratory function, and lean muscle mass in healthy adult men.^16-20 Prior placebo-controlled human trials have also supported the safety and benefit of combination therapy over monotherapy or placebo, suggesting a possible additive or synergistic effect of these two agents for safely improving muscle function in healthy human participants.^16-18 Prior to this study, testosterone combined with rHGH (combination therapy) had never been formally evaluated in any muscular dystrophy population. In this study, we report the findings of a 36-week single-arm Study of Testosterone and rHGH in FSHD (STARFiSH).

Methods

Study Design

We conducted an investigator-initiated, single-center, single-arm, proof-of-concept study to evaluate the safety and tolerability of daily rHGH (Genotropin) combined with testosterone enanthate injections every 2 weeks in men with FSHD. Participants received study drugs for 24 weeks, followed by a 12-week washout period. Participants completed serial safety and laboratory assessments, strength testing, functional assessments, and a disease burden questionnaire during the study.

The schedule of activities and evaluation is provided in eTable 1. After providing informed consent, participants attended a screening visit. Participants who met all eligibility requirements were enrolled and underwent in-person assessments at baseline, 8 weeks, 16 weeks, 24 weeks, and 36 weeks. Visit activities were standardized and completed in the same order and at the same time of day for each visit. Participants were instructed not to change their standard level of activity and exercise throughout the course of the study.

An independent safety monitor who is one of the authors, E. Ciafaloni, reviewed and monitored all safety and laboratory data. Elevations of IGF-1 higher than 400 ng/mL, total testosterone levels higher than 1,100 ng/dL, or a hematocrit level ≥54% were predetermined as criteria for mandatory study drug dosage reduction.

Study Participants

Twenty participants with FSHD (type 1) were recruited for this study from the University of Rochester Medical Center (URMC) and the National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members.²¹ Participant study enrollment occurred from February 5, 2018, to March 28, 2022. Inclusion criteria were as follows: (1) men between 18 and 65 years of age; (2) genetically confirmed FSHD or clinical symptoms suggestive of FSHD with a first-degree relative with genetically confirmed FSHD; (3) moderately affected (defined as ambulatory with detectable weakness on clinical examination), symptomatic, and ambulatory; (4) hematocrit ≤50%, prostate-specific antigen ≤4.0 ng/mL, fasting blood glucose <126 mg/dL; (5) ability to walk continuously for 6 minutes (cane or orthoses allowed); and (6) ability to independently administer intramuscular and subcutaneous injections (or have a designated person capable and willing to administer these injections).

Exclusion criteria were as follows: (1) diabetes, obesity (BMI > 35 kilograms/m²), or cardiovascular disease (heart failure, coronary artery disease, uncontrolled hypertension, untreated hypercholesterolemia); (2) untreated thyroid disease; (3) history of deep vein thrombosis; (4) untreated severe sleep apnea; (5) past pituitary disease; (6) significant musculoskeletal injury and/or pain that affects walking; (7) systolic blood pressure >160 mm Hg or diastolic pressure >100 mm Hg; (8) plans to dramatically change exercise habits; (9) liver disease; (10) psychiatric disease; (11) renal disease; (12) severe lower urinary tract symptoms (International Prostate Symptom Score > 19); (13) cancer (other than basal cell skin cancer); (14) plans to conceive; (15) heavy alcohol use (> 50 grams/day); (16) current use of testosterone or HGH; (17) testosterone level ≥1,100 ng/dL; or (18) current use of medications that interfere with the growth hormone or gonadal endocrine axis.

Study Drug Formulation

Participants were provided with rHGH (Genotropin) and testosterone enanthate study medications, along with syringes, needles, Genotropin pens, and other associated materials at their baseline visit.

rHGH and Genotropin pens were supplied by Pfizer Inc., and generic testosterone enanthate injections were purchased. Both drugs were packaged, labeled, and distributed to the investigators by the University of Rochester Investigational Drug Services unit. Investigators then disseminated the medications and supplies to enrolled participants after they had been trained to administer the combination therapy.

rHGH was administered via daily subcutaneous injections by participants (or their caregivers) at a dosage of 5.0 μg/kilogram (calculated using the participant's screening weight). Testosterone enanthate in oil was administered via intramuscular injections by participants (or their caregivers) every 2 weeks at a dosage of 140 mg. Participants took study medications from baseline until week 24. They were monitored during this period as well as throughout the washout period (during which study medications were stopped) from weeks 24 to 36.

Safety and Tolerability

The primary objective of this study was to evaluate the safety and tolerability of rHGH and testosterone combination therapy in adult men with FSHD. Adverse events, attribution of adverse events to the study drug, and actions taken regarding the study drug (dosing changes) were noted. Serious adverse events (death, life-threatening adverse event, persistent or significant disability/incapacity, or participant hospitalization/prolongation of existing hospitalization) were documented. In addition, blood and urine samples were obtained at each study visit for clinical safety laboratory assessments (complete metabolic panel, complete blood count, and urinalysis). Furthermore, participants were monitored for potential treatment-specific side effects, including peripheral edema, carpal tunnel syndrome, gynecomastia, insulin resistance, arthralgia, increased erythropoiesis, reduced high density lipoprotein (HDL) changes in cholesterol, elevated prostate-specific antigen, and elevated blood pressure.

Biomarkers: Lean Body Mass (DEXA) and Pharmacokinetics

Lean body mass (LBM) and fat mass were measured via dual-energy X-ray absorptiometry (DEXA). DEXA provides a practical and effective approach to determine and monitor LBM and has been used in prior neuromuscular disease clinical trials.^22-25 The pharmacokinetics of combination therapy in participants with FSHD were monitored by serial serum levels of free and total testosterone and IGF-1. Thyroid studies, fasting insulin levels, creatine kinase, C-reactive protein, luteinizing hormone, and follicle stimulating hormone levels were also monitored throughout the study.

Exploratory Measures of Clinical Efficacy

Exploratory measures of clinical efficacy included changes from baseline in composite manual muscle testing (MMT) scores,²⁶ composite quantitative muscle testing (QMT) scores,²⁷ FSHD-Composite Outcome Measure (FSHD-COM; total and individual test scores),^27-36 Epworth Sleepiness Scale score,³⁷ Fatigue Severity Scale score,³⁸ Beck Depression Inventory score,³⁹ FSHD Health Index (FSHD-HI; total and subscale scores),^40,41 PROMIS-57 scores,⁴² forced vital capacity (FVC), and International Physical Activity Questionnaire scores.⁴³ A description of each of these measures is given in eMethods.

Statistical Analysis

Statistical analysis was completed by M.P. McDermott and N. Dilek. The criterion for declaring combination treatment safe and well tolerated was determined prior to initiation of the STARFiSH trial. This criterion was based on a hypothesis test that compares the observed tolerability rate against a tolerability rate that would be considered unacceptably low, in this case 70%. A test based on the binomial distribution was performed for H₀: π ≤ 0.70 vs H₁: π > 0.70, where π is the true probability of tolerability, i.e., completion of the trial on treatment. The null hypothesis of unacceptable tolerability is rejected if the number of participants tolerating the dosage is 18 (of 20) or greater. This rule provided 80% power to detect that combination treatment was tolerable (had a tolerability rate >70%) if the true tolerability rate was 92%. The actual significance level of this test was 3.6%. Adverse events and laboratory tests, vital signs, and echocardiogram (EKG) abnormalities were summarized descriptively.

Changes from baseline in all serum markers and in LBM obtained using DEXA were the objective markers used to determine whether combination treatment showed sufficient promise to consider in further studies in FSHD. These outcomes were analyzed using a mixed-model repeated measures strategy, with time (treated as a categorical variable) as the factor of interest.⁴⁴ The covariance matrix for the within-participant observations was modeled using an unstructured pattern. Ninety-five percent CIs for mean changes from baseline to each visit were computed using this model, with the 24-week time point being of primary interest. Tests for significance of the mean changes from baseline to 24 weeks were, likewise, performed with this model using a significance level (2-tailed) of 5%. Exploratory analyses of potential efficacy, related to strength, function, sleep, fatigue, depression, and patient-reported outcomes, were performed in a similar manner.

Compliance

Participants kept a medication log and recorded any missed doses of study medication. They were instructed not to replace missed doses and to continue their dosing regimen as instructed. Missed doses and methods for mitigating future missed doses were discussed on weekly participant calls. In addition to self-report, compliance was assessed by tracking dispensed and unused packets that participants returned at each in-person visit. In addition, laboratory study response (e.g., increases in IGF-1 levels and testosterone levels) was serially monitored as a marker of study medication compliance.

Standard Protocol Approvals, Registrations, and Participant Consents

Local institutional review board approval was obtained at the URMC, and all participants provided written informed consent. This study is registered on ClinicalTrials.gov as “Study of Testosterone and rHGH in FSHD (STARFiSH),” with registration ID NCT03123913. The study protocol was submitted to the registry on September 25, 2017, and the first participant was enrolled on February 5, 2018. The study protocol and statistical analysis plan are available in the eSAP.

Data Availability

Any anonymized data not included in the article or online-only supplemental material will be shared, according to good clinical practice, with qualified investigators on request.

Results

Participant Demographics

Of the 20 participants initially enrolled in this study, 19 completed the study protocol. All participants were evaluated between February 5, 2018, and March 28, 2022. One participant dropped out after their baseline visit because of multiple factors, including travel distance, concern over the Coronavirus disease (COVID-19 or SARS-CoV-2) pandemic, and a perceived absence of benefits from the study treatments. Of the 100 expected study visits, 94 visits were completed. Four visits were not completed by the 1 participant who withdrew, and 2 participants each missed their week 8 visits because of the COVID-19 pandemic (unwillingness to travel to the site); however, for these 2 participants, a few assessments were performed remotely, including elicitation of adverse events. Participant demographic and clinical characteristics at baseline are summarized in Table 1. While most of the participants had smallest 4q35 allele sizes between 12 and 33 kb, which is characteristic of FSHD, one participant had a borderline allele size of 40 kb while demonstrating clear clinical signs of FSHD, including pronounced scapular winging, limited shoulder abduction, upper extremity weakness, and reduced grip function.

Table 1.

STARFiSH Participant Baseline Demographic and Clinical Characteristics

No. of participants	20
Age, yrs
Mean ± SD	41 ± 10
Range	27–61
Years since symptom onset
Mean ± SD	22.8 ± 10.6
Range	4–40
Years since diagnosis
Mean ± SD	10.9 ± 9.4
Range	2–40
Race, no. (%)
White	19 (95)
Other	1 (5)
Ethnicity, no. (%)
Non-Hispanic	20 (100)
Education level, no. (%)
High school	1 (5)
Technical school	1 (5)
College (some school, associate degree, or bachelor's degree)	13 (65)
Master's or doctorate	4 (20)
Omitted	1 (5)
Employment status, no. (%)
Employed full-time	14 (70)
Employed part-time	2 (10)
Retired	1 (5)
Permanently disabled	2 (10)
Other (sabbatical)	1 (5)
Disability benefits, no. (%)
Yes	3 (15)
No	17 (85)
Marital status, no. (%)
Never married	6 (30)
Married	11 (55)
Divorced	3 (15)
Molecular diagnostics: smallest 4q35 allele on the DNA test of participants (n = 18)a
Mean (kb) ± SD	25.4 ± 6.3
Range (kb)	12–40
Baseline clinical characteristics, mean ± SD
DEXA lean body mass/height2 (kilograms/m2)	15.6 ± 1.7
DEXA fat mass/height2 (kilograms/m2)	8.9 ± 3.1
Six-minute walk distance (m)	485.7 ± 96.2
FSHD-COM score	19.1 ± 13.4
Composite QMT (% of predicted normal) score	54.1 ± 25.2
Composite MMT score	4.37 ± 0.46
FSHD-HI	31.2 ± 17.1
Testosterone (pg/mL)	432.3 ± 181.7
Free testosterone (pg/mL)	81.3 ± 27.5
IGF-1 (ng/mL)	193.1 ± 35.7

Abbreviations: DEXA = dual-energy X-ray absorptiometry; FSHD-HI = FSHD Health Index; MMT = manual muscle testing; QMT = quantitative muscle testing.

^aAll 20 enrolled participants were genetically confirmed to have FSHD; 2 of the reports did not include 4q35 allele size. Individual participant allele sizes are included in eTable 2.

Safety and Tolerability

Of the 19 participants who completed the study, none experienced a serious adverse event or discontinued treatment.

Study drug dosages were reduced for several participants because of abnormal laboratory test results. rHGH and testosterone were reduced for 1 participant because of elevated hematocrit. rHGH alone was reduced for five participants: three because of elevated IGF-1, one because of glucose in the urine, and one because of elevated HbA1c. rHGH was temporarily held for one participant because of a transient rash after an upper respiratory illness. Lastly, testosterone dosage was reduced for one participant because of an elevated testosterone level (>1,100 ng/dL) seven days after his testosterone administration. In all cases, laboratory values were corrected after dosage modification. The reported adverse events are listed in Table 2, with injection site reaction being the most commonly reported (n = 7, 35%).

Table 2.

Adverse Events

Adverse event	No. affected	% Affected
Injection site reaction	7	35
Pain	2	10
Soreness	2	10
Flu-like symptoms	2	10
Cough	2	10
Edema limbs	2	10
Increased appetite	2	10
Muscle cramps	2	10
Decreased energy	1	5
Fatigue	1	5
Exercise fatigue	1	5
Itchiness	1	5
White patches on tongue	1	5
Nasal congestion	1	5
Sore throat	1	5
Palpitations	1	5
Nausea	1	5
Urine discoloration	1	5
Paresthesia	1	5
Headache	1	5
Vivid dreams	1	5
Irritability	1	5
Poison ivy	1	5
Rash	1	5
Fall	1	5
Weight gain	1	5

Exploratory Outcome Measures

After 24 weeks, LBM increased by 2.21 kilogram (95% CI 1.35–3.07; p < 0.0001) (Figure 1A); fat mass decreased by 1.30 kilograms (95% CI -2.56 to −0.04; p = 0.04) (Figure 1B); 6-minute walk distance increased by 37.3 m (95% CI 18.3–56.9; p = 0.001) (Figure 1C); function FSHD-Composite Outcome Measure (FSHD-COM) score improved by 2.4 points (95% CI −4.0 to −0.8; p = 0.006) (Figure 1D); overall strength (composite QMT, average % of predicted normal) increased by 3% (95% CI 0.3–5.6; p = 0.03) (Figure 2A); lower extremity strength (composite MMT lower extremity) increased by 0.13 points (95% CI 0.05–0.22; p = 0.004) (Figure 2B); and total patient-reported disease burden (FSHD-HI) improved by 6.1 points (95% CI −12.0 to −0.2; p = 0.04) (Figure 2C). Changes in IGF-1 and testosterone are shown in Figure 3, A and B. Changes in each of the outcome measures between baseline and 24 weeks, along with p values and CIs, are provided in Table 3. Due to the COVID-19 pandemic, forced vital capacity testing was discontinued as part of the protocol and is, therefore, not included in Table 3.

Figure 1. Mean Changes From Baseline in Body Composition, Ambulation, and Clinical Function.

Change in (A) lean body mass, (B) fat mass, (C) 6-minute walk distance, and (D) FSHD-COM score. FSHD-COM = FSHD-Composite Outcome Measure.

Figure 2. Mean Changes From Baseline in Strength and Disease Burden.

Change in (A) QMT % predicted normal, (B) MMT lower extremity score, and (C) FSHD-HI. FSHD-HI = FSHD Health Index; MMT = manual muscle testing; QMT = quantitative muscle testing.

Figure 3. Mean Changes From Baseline in Biomarker Levels.

Change in (A) IGF-1 and (B) free testosterone.

Table 3.

Mean Changes in Outcome Measures From Baseline to 24 Weeks

Outcome measure	Direction of favorable effect	Mean	SD	95% CI	p Value
DEXA lean mass (kilograms)*	Positive	2.21	1.80	(1.35 to 3.07)	<0.0001
DEXA fat mass (kilograms)*	Negative	−1.30	2.62	(−2.56 to −0.04)	0.04
Average MMT score	Positive	0.06	0.12	(−0.00 to 0.12)	0.05
Average MMT score–lower*	Positive	0.13	0.18	(0.05 to 0.22)	0.004
Average MMT score–upper	Positive	0.00	0.12	(−0.06 to 0.06)	0.94
QMT average percent of predicted normal*	Positive	2.95	5.54	(0.28 to 5.62)	0.03
QMT average percent of predicted normal–lower	Positive	3.29	8.66	(−0.89 to 7.46)	0.12
QMT average percent of predicted normal–upper*	Positive	2.78	5.17	(0.29 to 5.27)	0.03
FSHD-COM total score*	Negative	−2.37	3.32	(−3.97 to −0.77)	0.006
Distance walked in 6 minutes (meters)*	Positive	37.56	40.13	(18.21 to 56.90)	0.001
Distance walked in 2 minutes (meters)*	Positive	11.64	21.59	(1.24 to 22.05)	0.03
Timed up and go (seconds)	Negative	−0.36	1.14	(−0.91 to 0.19)	0.19
Self-selected gait speed (centimeters/second)	Positive	3.94	18.60	(−5.52 to 13.40)	0.39
Time to go 30 feet (S)	Negative	−0.04	0.45	(−0.26 to 0.17)	0.67
Time to ascend 4 steps (seconds)	Negative	−0.06	1.16	(−0.62 to 0.50)	0.83
Time to descend 4 steps (seconds)	Negative	−0.11	0.39	(−0.30 to 0.07)	0.22
Time from supine to sitting (seconds)	Negative	−0.14	0.62	(−0.44 to 0.16)	0.34
Time from sitting to standing (seconds)	Negative	0.31	1.17	(−0.26 to 0.87)	0.27
Time to pick up a penny (seconds)	Negative	−0.06	0.31	(−0.20 to 0.09)	0.44
Time to don/doff coat (seconds)	Negative	−0.60	4.79	(−2.91 to 1.71)	0.59
Beck Depression Inventory (BDI)*	Negative	−1.69	3.08	(−3.21 to −0.17)	0.03
Fatigue Severity Score (FSS)	Negative	−0.34	3.11	(−1.87 to 1.19)	0.65
Epworth Sleep Scale (ESS)	Negative	−0.85	2.68	(−2.15 to 0.46)	0.19
PROMIS-57 physical score (T score)	Negative	1.51	3.66	(−0.31 to 3.32)	0.10
PROMIS-57 anxiety score (T score)	Negative	−1.44	7.87	(−5.27 to 2.38)	0.44
PROMIS-57 depression score (T score)	Negative	−0.81	6.20	(−3.85 to 2.23)	0.58
PROMIS-57 fatigue score (T score)*	Negative	−5.74	6.90	(−9.11 to −2.37)	0.002
PROMIS-57 sleep disturbance score (T score)*	Negative	−3.15	5.43	(−5.84 to −0.46)	0.02
PROMIS-57 social satisfaction score (T score)	Negative	1.62	5.50	(−1.04 to 4.29)	0.22
PROMIS-57 pain interference score (T score)*	Negative	−6.53	8.92	(−10.88 to −2.19)	0.005
FSHD-HI total score*	Negative	−6.08	12.14	(−11.96 to −0.21)	0.04
FSHD-HI short-form score	Negative	−5.20	16.11	(−13.01 to 2.61)	0.18
FSHD-HI activity limitation	Negative	−6.17	18.25	(−14.98 to 2.65)	0.16
FSHD-HI mobility/ambulation	Negative	−5.20	12.74	(−11.36 to 0.97)	0.09
FSHD-HI shoulder/arm function*	Negative	−11.36	20.06	(−21.06 to −1.65)	0.02
FSHD-HI body image	Negative	−7.14	16.12	(−14.97 to 0.69)	0.07
FSHD-HI cognitive function	Negative	−2.79	9.17	(−7.27 to 1.70)	0.21
FSHD-HI communication	Negative	−1.58	15.77	(−9.25 to 6.09)	0.67
FSHD-HI core strength/function*	Negative	−10.39	17.27	(−18.76 to −2.03)	0.02
FSHD-HI emotional health	Negative	−0.02	12.17	(−5.97 to 5.92)	0.99
FSHD-HI fatigue*	Negative	−11.51	19.02	(−20.73 to −2.28)	0.02
FSHD-HI gastrointestinal function	Negative	0.16	4.30	(−1.98 to 2.29)	0.88
FSHD-HI hand/finger function	Negative	2.32	9.98	(−2.56 to 7.20)	0.33
FSHD-HI pain*	Negative	−9.46	14.38	(−16.48 to −2.44)	0.01
FSHD-HI social performance	Negative	−2.99	18.98	(−12.17 to 6.20)	0.50
FSHD-HI social satisfaction	Negative	−2.28	17.12	(−10.57 to 6.00)	0.57

Abbreviations: DEXA = dual-energy X-ray absorptiometry; FSHD-HI = FSHD Health Index; MMT = manual muscle testing; QMT = quantitative muscle testing.

Outcome measures and the direction of favorable effect are listed along with the mean, SD, 95% CI, and p value for each measure.* Statistically significant, with p < 0.05 indicated with an asterisk.

Six-minute walk distance, composite QMT score, and composite MMT lower extremity score demonstrated interval improvements throughout the 24-week period on study medications (Figures 1C and 2, A, B). During the 12-week washout period, measures of LBM, fat mass, strength, function, and patient-reported disease burden trended toward baseline but remained improved compared with initial baseline values and statistically significantly improved in the cases of 6-minute walk distance, FSHD-COM, composite MMT lower extremity score, and FSHD-HI (Figures 1, C, D and 2, B, C).

Discussion

In the investigator-initiated, single-center, single-arm, proof-of-concept study, rHGH combined with testosterone (combination therapy) was found to be safe and well tolerated in a well-defined sample of participants with FSHD.

STARFiSH participants were observed to experience improvements in ambulation, strength, LBM, and disease burden (quantified using the FSHD-HI) over a 24-week period without experiencing any serious adverse events. In addition, participants maintained improvement over baseline in many of these areas after a 12-week washout period. Placebo-controlled trials are needed to further investigate this encouraging therapeutic approach.

There are currently no available treatments that improve weakness, muscle atrophy, fatigue, and functional decline in FSHD. While the evaluation of disease-specific genetic-modifying treatments for FSHD is ongoing, these investigative treatments have not yet been shown to safely mitigate disease progression. Furthermore, it is unknown how much of an effect (if any) future genetic-modifying therapies will have on the recovery of lost muscle strength, muscle mass, fatigue, and muscle function.

Multiple agents given simultaneously may be needed to limit disease progression and improve clinical function in participants affected by FSHD. This approach has been successfully demonstrated in many other areas of medicine. Multiple agent therapy is now a cornerstone of both HIV/AIDS and cancer treatments. For participants with HIV, multiple pharmaceutical therapies are commonly used simultaneously to limit the progression of disease.⁴⁵ In oncology, multiple agents are also used simultaneously to limit cancer progression and maximize function.⁴⁶ We anticipate that, in the future, the treatment of individuals with muscular dystrophy may also adopt a similar multiagent approach. Such a strategy could consist of pairing genetic therapies with a regenerative treatment strategy such as that used in STARFiSH.

The STARFiSH study suggests that gains in LBM and physical function are generated in response to combination therapy in participants with muscular dystrophy. Going forward, it will be important to replicate these results and show that combination therapy can meaningfully improve clinical function, not just LBM. As was learned from the trials of bimagrumab in inclusion body myositis, in which LBM increased over 52 weeks but there was no change in the 6-minute walk distance over that time or compared with placebo, it is important to evaluate clinical trials with outcome measures that are consequential to how a patient feels and functions.

Participant fatigue, as measured using the FSHD-HI and PROMIS-57 fatigue score, also improved after combination therapy. In our prior study of individuals with FSHD, fatigue was noted to occur in >93% of participants and was identified as one of the symptoms that has the greatest impact on their lives.⁴⁷ The discovery and innovation of combination therapy has significant implications because it has identified a way to potentially improve strength and function in those with FSHD while improving their fatigue and ability to walk. The verification of such an effect may change existing treatment paradigms and has the potential to help hundreds of thousands of people who struggle with the burden of FSHD. In short, if combination therapy is verified to limit the rate of functional decline in participants with FSHD through a future randomized, placebo-controlled trial, it would represent a therapeutic advance for those who currently struggle with this muscular dystrophy.

This study had some limitations. Our trial was conducted in the context of the COVID-19 pandemic. While we were able to successfully continue and finish the study, some protocol adjustments (including the elimination of FVC testing) were made to maximize the safety of participants and staff. It is also possible that some of the findings may have been affected, with participants likely experiencing changes in their social routines due to the pandemic. In addition, this was an open-label trial and involved a relatively small sample size, only men, and a relatively brief follow-up period. Additional larger and longer-term randomized studies are necessary to further investigate the effects of combination therapy in individuals with muscular dystrophy.

We suspect that, as a generic therapy, our combination therapy may have applications for other muscular dystrophies beyond FSHD. There is also evidence that hormones, such as estrogen, may improve the differential properties of FSHD-derived myoblasts by antagonizing DUX4 activity.⁴⁸ As such, future studies involving patients with FSHD should explore what disease-specific and DUX4 effects occur in response to rHGH and testosterone. Given that our study now provides preliminary safety and efficacy data regarding combination therapy in men with FSHD, a reasonable next step is to consider an evaluation of combination therapy for women with FSHD. While women would likely not tolerate the dosages of testosterone used in this study, lower dose testosterone replacement therapy has been used safely and effectively in women with hypoactive sexual desire disorder.⁴⁹ In addition, rHGH is approved for use in women with many conditions including growth hormone deficiency, Prader-Willi syndrome, idiopathic short stature, and Turner syndrome.⁵⁰ A carefully planned dose-finding study is needed to determine the safety and optimal dose of these medications for women with FSHD and determine whether the effects of combination therapy are comparable between men and women with muscular dystrophy.

The outcomes of this open-label 36-week study of testosterone and rHGH in FSHD indicate that this treatment approach is safe and well tolerated over 24 weeks and is promising as a therapy to combat and reverse impaired ambulation, weakness, muscle loss, and symptomatic burden in FSHD. Randomized, double-blind, placebo-controlled studies are warranted to further evaluate this multimodal treatment strategy for individuals with FSHD.

Glossary

DEXA

dual-energy X-ray absorptiometry

FSHD

facioscapulohumeral muscular dystrophy

FSHD-COM

FSHD-Composite Outcome Measure

FSHD-HI

FSHD Health Index

FVC

forced vital capacity

HGH

human growth hormone

LBM

lean body mass

MMT

manual muscle testing

QMT

quantitative muscle testing

rHGH

recombinant human growth hormone

STARFiSH

Study of Testosterone and rHGH in FSHD

URMC

University of Rochester Medical Center

Author Contributions

C.R. Heatwole: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data. E. Luebbe: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. J. Hamel: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. P.C. Mongiovi: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. E. Ciafaloni: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. N. Dilek: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. W.B. Martens: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. D.R. Weber: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. H. Rashid: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. J. Allen McKeown: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data. C.H. Smith: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data. S. Howell: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data. S.Z. Rosero: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. K. Eichinger: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data. L.S. Baker: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data. J.M. Dekdebrun: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data. J.E. Hilbert: drafting/revision of the manuscript for content, including medical writing for content. A. Varma: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. C.A. Thornton: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. M.P. McDermott: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. R.T. Moxley Iii: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data.

Study Funding

Research reported in this publication was supported by the NINDS of the NIH under award number R01NS095813.

Disclosure

Chad Heatwole receives royalties for the use of multiple disease-specific instruments. He has provided consultation to Biogen Idec, Ionis Pharmaceuticals, aTyr Pharma, AMO Pharma, Acceleron Pharma, Cytokinetics, Expansion Therapeutics, Harmony Biosciences, Regeneron Pharmaceuticals, Astellas Pharmaceuticals, AveXis, Recursion Pharmaceuticals, Iris Medicine, Inc., Takeda Pharmaceutical Company, Scholar Rock, Avidity Biosciences, Novartis Pharmaceuticals Corporation, SwanBio Therapeutics, Neurocrine Biosciences, Sanofi, Lupin Pharmaceuticals, Vertex Pharmaceuticals, Dyne Therapeutics, Applied Therapeutics, and the Marigold Foundation. He receives grant support from the Department of Defense, Duchenne UK, Parent Project Muscular Dystrophy, Recursion Pharmaceuticals, Swan Bio Therapeutics, Sanofi, Lupin Pharmaceuticals, the NINDS, the Muscular Dystrophy Association, the Friedreich's Ataxia Research Alliance, Cure Spinal Muscular Atrophy, the Amyotrophic Lateral Sclerosis Association, the University of Miami, Novartis Pharmaceuticals Corporation, and the M.J. Foxx Foundation. He is the director of the University of Rochester's Center for Health + Technology. E. Luebbe has no disclosures. J. Hamel consults for Vertex Pharmaceuticals. P. Mongiovi has no disclosures. E. Ciafaloni has received personal compensation for serving on advisory boards, on DMCs, and/or as a consultant for Alexion, Argenx, Biogen, Momenta, Pfizer, Sarepta Therapeutics, Janssen, Italfarmaco, NS Pharma, Regenxbio, and ML Bio Solutions. N. Dilek, W. Martens, D. Weber, H. Rashid, J. Allen, C. Smith, S. Howell, and S. Rosero report no disclosures. K. Eichinger has received personal compensation for serving on advisory boards and/or as a consultant for Fulcrum Therapeutics, Avidity Biosciences, Roche, Dyne Therapeutics, and TRiNDS. She has received royalties for the FSHD-COM. L. Baker has no disclosures. J. Dekdebrun consults for Avidity Biosciences, Arthex, Dyne Therapeutics, Lupin, Pepgen, Vertex Pharmaceuticals, TRiNDS, and Atom. J. Hilbert and A. Varma report no disclosures. C. Thornton provides consulting to Biogen, Vertex Pharmaceuticals, Entrada Therapeutics, and Avidity Biosciences; received honoraria from Sanofi; served on Scientific Advisory Boards for Dyne Therapeutics and PepGen; and serves on the Board for the Myotonic Dystrophy Foundation. M.P. McDermott receives grant funding from the NIH, FDA, and Cure SMA and has served on Data and Safety Monitoring Boards for NIH, Eli Lilly and Company, Neurocrine Biosciences, Inc., ReveraGen BioPharma, Inc., NS Pharma, Inc., Prilenia Therapeutics Development, Ltd., and Seelos Therapeutics, Inc. R.T. Moxley has no disclosures. Go to Neurology.org/NG for full disclosures.

TAKE-HOME POINTS

• → This study investigates the safety, tolerability, and preliminary efficacy of testosterone and rHGH combination therapy in adult men with facioscapulohumeral muscular dystroph (FSHD).

• → In this proof-of-concept clinical trial of 20 participants with FSHD, the combination therapy was well tolerated with no serious adverse events. After 24 weeks, lean body mass (LBM), 6-minute walk distance, overall strength, clinical function, and disease burden improved from baseline.

• → The use of combination therapy for FSHD to recover muscle mass, ambulation, and function holds promise and warrants further study through a larger, randomized controlled trial.