Efficacy and safety of ornithine alpha-ketoglutarate in heel pressure ulcers in elderly patients: Results of a randomized controlled trial

Abstract

Objective

Pressure ulcers affect predominantly the elderly and nutritional status is a known risk factor. Guidelines on pressure ulcers provide recommendation on nutritional management. Ornithine alpha-ketoglutarate (OKG) is an adjuvant treatment in undernourished elderly patients or in patients with hypercatabolism states. It is a precursor of different amino-acids which play a role in the process of healing. The objective of the study is to determine the efficacy of OKG on pressure ulcer area reduction after six weeks of treatment.

Design

Multi-centre, international, randomized, comparative, double blind, parallel groups, placebo-controlled study.

Participants

160 patients (ITT population) aged over 60 years with a heel pressure ulcer at stage II or III.

Intervention

Patients received OKG (n=85) or placebo (n=75) once a day for 6 weeks.

Measurements

Ulcer area was measured each week, using a tracer. The primary endpoint was the percentage reduction of the surface at the final visit: [(Wound areatn — Wound areat0)/(Wound areat0)].

Results

At inclusion, ulcer area distribution deviated from normal distribution (median ulcer area OKG 6.6cm², placebo 3.9 cm², p=0.044, Mann-Whitney test). As healing is strongly related to baseline ulcer area, the abnormal distribution was a major bias. Therefore it was decided to perform the analysis on 2 sub-groups of patients according to the mean ulcer area, i.e. above or below 8cm². The mean wound area reduction for baseline area ≤ 8 cm² are −59. 5 ± 71.4% and −54.0 ± 69.0% for the OKG group and placebo groups respectively (p=0.477, Mann-Whitney test). In the group with baseline pressure ulcer area > 8 cm² no between group differences on either parameter was detected. When closure rate is considered, a significant difference in favor of OKG group is observed (− 0.07 cm²/day in the OKG group and − 0.04 cm²/day in the placebo groups respectively p=0.007, Mann-Whitney test). Thirty serious adverse events were reported in 28 patients (15 allocated to OKG and 13 to placebo). None of them was considered treatment related.

Conclusion

This clinical trial supports a potential benefit of OKG 10g daily in the subgroup of patients with pressure ulcers ≤ 8 cm² surface area in elderly population when associated with debridement together with wound management according to pressure ulcer guidelines. However this study highlights methodological difficulties to perform clinical trials in old-old patients that may affect the robustness of the results for this type of study.

Introduction

Pressure ulcers are a common problem in both acute and long-term care facilities, 60 to 70% of the patients affected are elderly (1). Nutritional status is among the most consistently reported risk factors associated with increased pressure ulcer incidence (2). Nutritional status is often poor in patients with pressure ulcer, and systemic inflammation is common. IL6 blood levels are significantly increased. IL6 produced locally in damaged areas together with cortisol may aggravate malnutrition and hypercatabolism in patients with pressure ulcers. (3)

The management of pressure ulcers includes both local and general treatment, and should take into account the patient and the wound (4, 5, 6).

The main element of wound treatment is offloading using positioning and pressure relieving system. The optimal local treatment refers to debridement, cleansing and covering the wound with a dressing appropriately selected in function of the wound characteristics and promoting a moist environment.

Pain should be managed appropriately and analgesics should be used in accordance with the WHO three-level approach. The nutritional status can be readily influenced by patients and caregivers and managed as recommended by the guidelines. Although data derived from clinical assessments documenting the influence of nutritional management including protein intake on the course of pressure ulcers are limited (7, 8), it has been shown that standard care in nutrition and physical activity for hospitalized patients, resulted in improvement of daily living autonomy at discharge. (9)

The guidelines recommend a protein intake of 1.2 to 1.5 g per kg and per day (4). EPUAP guidelines recommend a minimum of 30–35 kcal/kg of body weight/day, with protein intake of 1.5 g/kg/day and 1 ml/kcal/day of fluid intake in patients with a pressure ulcer (6).

Ornithine alpha-ketoglutarate (Cétornan®, CHIESI Pharmaceutical, France) has been developed in France as a drug and granted a Marketing Authorization and the status of a reimbursed drug. OKG is indicated as an adjuvant treatment in undernourished elderly patients or in patients with hypercatabolism states (10, 11). OKG optimizes the efficiency of nutritional intake and accelerates the improvement in nutritional status (12).

OKG, an amino acid salt composed of 2 molecules of ornithine for 1 molecule of alpha-ketoglutarate, plays a multifactorial role in the treatment of wounds. It is a precursor of glutamine, arginine, which presents immunostimulant properties and which promotes healing, aliphatic polyamines, including proline, which play a fundamental role in the control of the cell multiplication process. Ornithine alpha-ketoglutarate also stimulates the secretion of insulin and growth hormone (13, 14, 15).

The clinical efficacy of treatment with OKG in wound healing has been evaluated in various clinical settings including patients with burns, plastic and reconstructive surgery in head and neck cancer (16, 17, 18, 19). When assessed in burn patients, OKG treatment (10-20 g/d) normalizes plasma concentrations of amino acids and improves visceral protein levels and nitrogen balance. It is suggested that the anabolic properties of OKG are in relation with its ability to increase protein synthesis rate, to counteract protein hypercatabolism and to spare the glutamine pool (19).

One previous open randomized controlled trials comparing OKG to standard cares and four randomized double-blind trials comparing OKG to placebo suggested a clinical relevant impact of this treatment on pressure ulcer healing (20, 21). When pooling these data, 67.1% of pressure ulcers allocated to OKG decreased by at least 40% at last planimetric measurement as compared to 46.3% in control group (OR: 2.32; 95%CI:1.20 / 4.49; p=0.01). Although the results observed on the healing rate were in favor of OKG, these trials were performed in a single center, on small sample sizes, on heterogeneous wounds in terms of location and baseline stages (20, 21).

In view of the methodological limitations of these trials, the efficacy of OKG needed to be evaluated in a multicenter, double-blind, placebo-controlled trial conducted on a larger population of elderly subjects.

Method

Study design

This was a multicenter, comparative, randomized, double-blind trial, conducted on parallel groups, with a treatment duration of six weeks. This trial was conducted in geriatrics, internal medicine, physical medicine and rehabilitation, trauma, plastic surgery, cardiology, neurology and dermatology settings.

The primary objective was to document the effect of OKG on heel pressure ulcer area reduction after 6 weeks of treatment versus placebo. The heel localization was intended to better standardize the patient population. The secondary objectives were:

• -To study the related endpoints: global closure rate, closure rate at each visit, cumulative closure rate, ulcer with 40% or 90% area reduction.
• -To measure the efficacy of administration of OKG on clinical/laboratory parameters reflecting the patient’s nutritional and inflammatory status
• -To document safety of OKG in the treatment of pressure ulcers

Study population

Hospitalised patients or outpatients were eligible to participate to this study if they met the following criteria:

• •Males or females over the age of 60 years who have given their written informed consent to participate in the trial
• •Heel pressure ulcer (NPUAP Stage II or III) occurring after accidental immobilization
• •Ulcer in the process of recovery with early signs of granulation tissue (at least 10% of red tissue on colour scale).

Exclusion criteria:

• •Patients confined to bed 24 hours a day before the episode triggering development of the pressure ulcer
• •Pressure ulcer entirely covered by necrosis or fibrin, infected ulcer
• •Poorly controlled type I or II diabetes, dialysed patient, active neoplastic disease,
• •parenteral nutrition,
• •Serum albumin <22 g/l.
• •Advanced peripheral arterial occlusive disease [ABPI (ankle brachial pressure index) ranging between 0.80 and 1.3 with presence of distal pulses]

This study was conducted in concordance with the principles of good clinical practice and the Declaration of Helsinki.

Studied and concomitant treatments

One 10g sachet of ornithine alpha-ketoglutarate or one sachet of placebo (similar aspect and taste) was administered once daily during or after lunch, preferably in 200 ml of water or mixed with food.

Compliance was monitored by the investigating team during hospitalization. When the patient was followed on an outpatient basis, treatment kits were collected at each follow-up visit, all used sachets were counted to determine compliance with treatment.

Long-term corticosteroid therapies, other amino acids, anorectics, megestrol acetate, vitamin C, high-dose zinc to promote healing and omega-3 fatty acids were prohibited during study course.

Dressings and local care

During this study, the following protocol was followed:

• •Ulcer management was in accordance with the French consensus conference (November 2001). Mechanical debridement of necrotic tissues was performed as necessary. Cleaning was performed with physiological saline and Betadine was used for local care. Heel elevation was performed systematically. The choice of dressings was adapted to the state of the wound. The frequency of dressing changes was adapted to the volume of exudates, the type of dressing and the course of the wound.
• •Heel offloading was performed systematically and each patient was provided with a suspension boot to be worn when sitting or lying down (MedaBoot®).
• •Management of pain was implemented : analgesics were used and adapted according to the circumstances of onset of pain.
• •Topical corticosteroids for excessive granulation tissue and topical antibacterials were allowed for less than 2 consecutive weeks.

A protein intake of 1.2 to 1.5g/kg/day was recommended.

Clinical assessment

Patients were assessed at selection visit, randomisation visit, and once a week for six weeks.

• •At selection the following were measured: albumin, C reactive protein (CRP), pre-albumin, creatinine, glycated haemoglobin, distal ABPI (pocket Doppler) and three-day dietary record to calculate caloric and protein intakes. Braden score and mini nutritional assessment scale (MNA) were also recorded to document risk factors of pressure ulcer (PU).

  The overall Braden Scale score is obtained by totaling a numerical ratings from a 6 subscales. The lower the score, the higher the patient’s risk for developing a pressure ulcer. A total score is considering at risk between 15 to 18 (23). The MNA, which comprises eighteen questions, evaluates the nutritional status of the subject. The score range is 0–30 (<17, malnutrition; 17.5–23.5, risk of malnutrition; ≥24, well-nourished) (24).

• •At each visit the following ulcer parameters were recorded: clinical description, length and width (using a flexible graduated ruler), acetate tracing of the ulcer area and local care was recorded (including number of dressing changes and dressings used).
• •At visit 6, ulcer parameters were recorded and serum albumin, CRP, pre-albumin, optional 3-day dietary record, appetite assessment using visual analogical scale (VAS) and MNA were also evaluated, as were any adverse events.

Sample size determination

Based on the previous studies of OKG in the treatment of pressure ulcers (20, 21), a sample size of 70 patients per group (total of 140) was calculated as sufficient to detect an absolute difference between the OKG group and the placebo group ranging from 0.30 to 0.40 on the reduction of the planimetric surface area at 6 weeks compared to the baseline value (alpha risk 5%, beta risk 20%, bilateral test, power of the test 0.80 and 20% drop out rate).

Randomisation (1:1 ratio) was balanced by blocks of 4, randomization codes were generated by using CRISTAL software. A randomisation number was attributed according to the chronological order of entry of patients into the double-blind period within each investigational site.

Data processing and statistical analysis

Ulcer area tracing recorded by investigators were centrally and blindly measured by using AUTOCAD software. Two measurements were made by tracing (two independent evaluators) and the mean of the two values was used for analysis.

Analysis of the primary efficacy criterion was performed by ANCOVA using patient’s age, history of the lesion and patient’s weight as covariates. The primary endpoint was the percentage reduction of the surface at the final visit: [(Wound areatn – Wound areat0)/ (Wound areat0)].

Efficacy analyses were performed on the intent to treat (ITT) population defined and categorized before code breaking. The Last Observation Carried Forward (LOCF) principle was applied to deal with missing efficacy time-points.

Results

67 investigational centers from six European countries (Bulgaria 2; France 38; Germany 6; Italy 8; Romania 4; Spain 9) selected 194 subjects and randomized 165 of them: 89 allocated to OKG group and 76 to placebo (safety population). The 160 patients who took at least one dose of the study medication and who have at least one post-treatment evaluation constitute the ITT population (85 OKG group and 75 placebo).

Dropout rate was not statistically different between groups (40 OKG group and 32 placebo; p=0.278; 2 test) table 1.

Table 1.

Reasons to drop out during study course

visits FU weeks	V01 W01	V02 W02	V03 W03	V04 W04	V05 W05	V06 W06
Cetornan group	0	0	0	3	0	1
Adverse event	1	2	2	4	1	5
Completehealing	0	0	2	0	0	0
Death	0	0	0	0	0	0
Lost to follow-up	2	1	0	1	0	11
Not specified	0	0	0	0	1	0
Required by protocol	3	0	0	0	0	0
Withdrawal of consent
Total	6	3	4	8	2	17
Placebo group	0	0	0	1	1	0
Adverse event	0	0	4	2	2	4
Completehealing	1	2	0	0	0	0
Death	0	1	0	0	1	0
Lost to follow-up	0	0	0	1	4	4
Not specified	1	2	0	0	0	0
Required by protocol	1	0	0	0	0	0
Withdrawal of consent
total	3	5	4	4	8	8

Demographic and medical baseline characteristics

Baseline patients’ characteristics are summarized in table 2. Overall, the global mean age of the ITT population was 80.8 ± 8.8 years. Mean body weight (BW) was 65.1 ± 14.3 kg at inclusion. Body mass index (BMI) calculated by estimating height was 26.9 ± 6.2 kg/m². The statures of elderly persons were estimated from a recumbent mesure of knee height in men and knee height and age for women. (Chumlea formula) (25).

Table 2.

General baseline characteristics of the population

	OKG (n=85)	ITT population Placebo (n=75)	p
Sex (M/F) %	34.1/65.9	52.6/47.4	0.017
Age (years)	81 ± 8.2	80.5 ± 9.6	0.760
BMI	27.1 + 6.5	26.7 + 5.9	NS
ABPI	1.0 ± 0.2	1.0 ± 0.2	0.395
Braden score	17.6 ± 3.2	18 ± 3.2	0.408
Appetite evaluation
VAS patient (mm)	5.8 ± 2.1	6.3 ± 2.5	0.225
VAS investigator (mm)	6.5 ± 1.9	6.6 ± 2.2	0.768
MNA	17.7 ± 4	17.6 ± 4.6	0.987
Lab parameters
C-reactive protein (CRP)	25.53 ± 26.96	32.75 ± 39.17	NS
Serum albumin	32.65 ± 4.73	32.08 ± 5.5	NS
Serum creatinine	90.25 ± 42.07	92.49 ± 42.91	NS

Mean Braden score was of 17.8 ± 3.2 (range: 8 – 23). About 35.6% of the total ITT population had a Braden score lower than 17. According to MNA score, (150 complete MNA in the ITT population), nutritional status was poor (MNA <17) in 66 patients (44% of the ITT population).

All these baseline characteristics were well balanced between treatment groups, except for M/F sex ratio. The OKG group had a higher proportion of women but this does not affect the study results.

Wound characteristics at baseline

The main baseline characteristics of the target pressure ulcer (PU) are presented in table 3.

Table 3.

Baseline aspect of the target ulcer

		OKG (n=85)	ITT population Placebo (n=75)	p
Aetiology
Immobilisation due to a medical cause		57.6%	52.0%
Immobilisation following surgery		27.1%	29.4%
Immobilisation following trauma		15.3%	18.7%
Ulcer stage
II		38.8%	32.0%
II OR III		47.1%	53.3%	0.656
III		14.1%	14.7%
History (weeks)
Mean		13.1 ± 17.5	15.4 ± 24.1
Median		6.0	7.5	0.584
Min-Max		1 - 104	1 - 150
Local aspect
Normal appearance		40.0%	29.3%
Erythema/Redness		71.4%	75.0%
Oedema		59.5%	69.9%
Eczema		58.8%	68.9%
Maceration		76.9%	85.0%
Permanent local pain		2.9%	1.5%
Ulcer area (cm2)
Mean		8.7 ± 6.7	8.2 ± 8.9
Median		6.6	3.9	0.044
Min-Max		0.71 – 39.05	0.23 – 48.14
Log-transformed Ulcer area		0.816 ± 0.349	0.665 ± 0.494	0.027
Ulcer area by classes (%)
Area ≤4 cm2		25.9%	52.0%
>4 Area ≤8 cm2		29.4%	9.3%
>8 Area ≤12 cm2		18.8%	12.0%	0.001
>12 Area ≤16 cm2		17.6%	13.3%
Area >16 cm2		8.2%	13.3%
Subgroup of ≤8 cm2PU		N=47	N=46
Ulcer area (cm2)	Mean ± SD	4.2 ± 1.9	2.7 ± 1.7
	Median (range)	4.2 (0.7-7.7)	2.7 (0.2-7.8)
Subgroup of >8 cm2PU		N=38	N=29
Ulcer area (cm2)	Mean ± SD	14.3 ± 6.3	16.8 ± 8.8
	Median (range)	12.9 (8.0-39.1)	13.2 (8.2-48.1)

Most of these PU were secondary to a prolonged immobilization due to a medical condition or following surgery. This was the first episode in 93.3% of patients and another PU was present in 40% of cases.

Ulcer area distribution (figure 1) was unbalanced between groups with a significantly higher proportion of small ulcers in placebo group (52.0% had an area ≤ 4 cm²) compared to 25.9% in the OKG group. Overall, while arithmetic mean areas (but not medians) were close, non-parametric tests detected between-group differences (p=0.044) which were confirmed by parametric tests after log-transformation to normalize distribution (p = 0.027 for group comparisons).

Figure 1.

Ulcer area distribution at baseline

As baseline ulcer area is the strongest predicting factor for healing course (22), all estimators of this latter outcome (% decrease of ulcer area, absolute closure value, and healing rate) will be strongly biased in disfavor of the OKG group that cannot be corrected the use of baseline ulcer area as covariate.

Therefore, it was decided to discriminate two groups of pressure ulcers by using the mean pressure ulcer area of the whole study population as cut-off point ie 8cm² and to perform independent analysis on these groups. Accordingly, 58.1% of ulcers were classified within the ≤8 cm² group. This procedure will not compensate for between-group unbalanced ulcer area but will allow treatment effect comparisons on more homogeneous subgroups of wounds.

Wound area changes at six weeks: primary endpoint

In population with baseline PU area ≤8 cm², mean absolute decrease in wound area at week 6 was significantly greater in the OKG group compared to the placebo (-2.3 ± 4.2 cm² vs. -1.7 ± 1.7 cm²; p = 0.006). This difference in absolute decrease was significant from week 1 up to week 6. When % regression in wound area was calculated, no between-group difference was detected (-59.5 ± 71.4% and -54.0 ± 69.0% in the OKG and placebo groups respectively; p = 0.477). A trend of higher proportion of wounds reaching a > 90% regression by week 6 was seen in the OKG group (23.4% vs 13.0%) (OR=0.49; 95%CI= 0.16/1.46).

In the group with baseline PU area > 8 cm² no between group differences on either parameter was detected.

Closure rates

In population with baseline PU area ≤ 8cm², closure rate at week 6, calculated as [(Areat0-Areaw6)/Δt0-w6] was significantly higher in the OKG group compared to placebo (-0.07 ± 0.11 cm²/day vs. -0.04 ± 0.08 cm²/day; p = 0.007). This difference was clearly due to a higher weekly closure rate at week 1 and week 2 (figure 2).

Figure 2.

No difference between-group on closure rate was observed in the population with baseline PU area >8 cm² group.

Nutritional evaluation

There was a trend for MNA to slightly increase over time in both groups as well as for the mean scores of the Visual Analogical Scales evaluating patients’ appetite without between-group differences. Body weight remained unchanged in both groups.

No clinically relevant changes for serum albumin, serum pre-albumin and C reactive protein were observed in either group.

Figure 3.

Global closure rate in the ≤8 cm² area group. ITT population

Adverse events

A total of 347 adverse events AEs were reported in 105 patients, 33AEs reported in 22 patients (15 OKG, 7 placebo) were considered related to study medication. All this AEs were mild to moderate. The only clinically relevant difference observed was a higher incidence of gastrointestinal events in the OKG group. None were severe and only seven were considered as related to study treatment by investigators. Of interest, diarrhea, vomiting and nausea represent 68% and 67% of the total number of gastrointestinal AEs in OKG and Placebo groups respectively.

Thirty serious adverse events were reported in 28 patients (15 OKG, 13 placebo). All were regarded as unrelated to the studied medication. These serious adverse events included 8 fatalities (5 and 3 in OKG and placebo group respectively). Table 4 & 5.

Table 4.

Listing of deaths

Group	Year	Sex	Last fu week	Relation to Trt	AE outcome	Expecteded event	Preferred term
Cetornan	76	F	W01	Unrelated	Death unrelated to drug	Expected	Septic shock
Cetornan	93	F	W03	Unrelated	Death unrelated to drug	Unexpected	Cardiac failure cture
Cetornan	92	F	W06	Unrelated	Death unrelated to drug	Expected	Broncho pneumonia
Cetornan	85	M	W04	Unrelated	Death unrelated to drug	Expected	Sepsis
Cetornan	71	M	W03	Unrelated	Death unrelated to drug	Unexpected	Death
Placebo	77	M	W02	Unrelated	Death unrelated to drug	Unexpected	Acute pulmonary oedema
Placebo	69	M	W01	Unrelated	Death unrelated to drug	Expected	Septic shock
Placebo	68	F	W02	Unrelated	Death unrelated to drug	Expected	Infected skin ulcer

Table 5.

Other serious adverse events than deaths

Group	PT	Year/Sex	Severity	Drug related	Preferred term
Cetornan	1001	75/F	Severe	No	Lung infection
Cetornan	1001	75/F	Severe	No	Coma
Cetornan	1001	75/F	Severe	No	Phlebitis deep
Placebo	10204	92/M	Severe	No	Pulmonary embolism
Placebo	10502	74/F	Severe	No	Pulmonary oedema
Placebo	10504	83/M	Moderate	No	Tuberculosis
Cetornan	1602	86/M	Mild	No	Urinary retention
Placebo	1607	93/M	moderate	No	Abdominal strangulated hernia
Cetornan	1801	68/M	severe	No	Arteriopathic disease
Placebo	1803	94/M	moderate	No	Acute pulmonary oedema
Placebo	1803	94/M	moderate	No	Lung disorder
Cetornan	20101	77/F	severe	No	Ovarian neoplasm
Placebo	20402	75/M	Moderate	No	Urethritis
Placebo	2203	81/F	Severe	No	Tibia fracture
Placebo	30701	84/F	Severe	No	Acute respiratory failure
Cetornan	31701	85/F	Severe	No	Arterial occlusive disease
Cetornan	3403	90/F	Moderater	No	Subdural haematoma evacuation
Cetornan	3404	83/F	Moderate	No	Fall
Cetornan	50310	70/M	Moderate	No	Abscess limb
Placebo	5401	81/F	Mild	No	Colonoscopy
Cetornan	6201	78/F	Moderate	No	Femoral neck fracture
Cetornan	7201	88/F	Severe	No	Hip arthroplasty

Discussion

This study was conducted to evaluate pressure ulcer healing in a geriatric population treated with OKG or placebo. In order to limit the influence of selected high heterogeneity of wounds, this trial exclusively recruited pressure ulcers located at the heel, presenting at least some evidence of granulation. Major peripheral arterial disease was ruled out by excluding péripheral arterial occlusive disease, poorly control diabetes and severe renal insufficiency. In addition local treatment followed EPUAP guidelines and patients were equipped with similar offloading system.

Despite these cautions in planning this trial, three points must be discussed :

Recruitment

The mean age of the population was over 80 years and a high proportion of women were expected, this was true for the OKG group, however, inexplicably, the reverse was seen in the placebo group. Nevertheless, as healing process is not sex dependent, this difference will not affect the interpretation of the study outcomes. There is no clear explanation to the between-group unbalanced repartitions for gender. However, it should be noted that due to major difficulties in patient recruitment, the study was opened to many more centers than initially planned. The consequence was that 2/3 of the centers recruited no more than 2 patients while randomization was balanced by blocks of four.

Heterogenous ulcers at baseline

Randomization failed to properly balance baseline PU characteristics between groups.

Schematically, two populations were identified: the first characterized by an ulcer area ≤8 cm² and abundant granulation tissue and a second defined by larger ulcers and the presence of abundant necrotic tissue. In contrast to the first group, this latter population was clearly composed of ulcers at a debridement stage, not yet appropriately cleaned with limited chances to improve substantially within the following weeks. The global evolution of pressure ulcers in this study supported this interpretation. Whatever the treatment, 84.0% of the PU in the first population (≤8cm²) reached ≥ 40% wound area reduction at week 6 as compared to 64% in the second (>8cm²) group (p=0.004).

Ulcer sizes at baseline

Pressure ulcers in the OKG group were significantly larger compared to placebo group.

Therefore, it was decided to discriminate two groups of pressure ulcers by using the mean pressure ulcer area of the whole study population as cut-off point ie 8cm² and to perform independent analysis on these groups.

Since all planned study outcomes (e.g. % of reduction area, closure rate) are directly dependent on the value of the baseline ulcer area, the strong between-group baseline unbalanced repartition of this parameter precluded all further comparisons even when using baseline wound area as covariate.

Therefore, it was proposed in this study to conduct the statistical analysis by focusing on the sub-group of ulcers with a baseline area ≤8cm², i.e. the population that was expected to be recruited in this study (PU properly deterged with a reasonable chance to close within 6 weeks). Indeed, in a clinical trial including a limited number of patients, the chances to detect an effect when using a treatment potentially promoting healing such as OKG is possible only with wounds that have a potential to be cured.

This analysis has documented a “booster” effect of OKG characterized by a higher closure rate during the first two weeks compared to placebo. This early advantage was then maintained in the following weeks so that the global closure rate over the total 6-week period was significantly better in the OKG group. Furthermore, there was a clear trend to observe in the OKG group a better chance to reach a ≥ 90% area reduction at week 6.

In this study, the pressure ulcers were treated in accordance with good clinical practices and guidelines with a standardised program of appropriate wound care (control of infection, sharp debridement, provision of a moist environment and avoidance of pressure on the wound). OKG has been effective in the treatment of acute wounds in patients with hypercatabolic states, improving the nitrogen balance in surgical, burn, septic and poly-trauma patients. The OKG studies in pressure ulcer including this one suggest an effect in chronic wound as well.

With regard to the the side-effects, OKG appeared to be well tolerated in this population. The only detected effects possibly related to this treatment were transient episodes of diarrhea, vomiting or nausea. These side effects are already well known with OKG and occurred mainly at treatment initiation.

When conducting clinical studies in such elderly patients, methodological difficulties should be taken into consideration in particular recruitment of subjects with an acceptable life expectancy and mild to moderate (rather than severe) concomitant disease, and the difficulty to perform randomization due to high heterogeneity of the selected wounds (in terms of grade, evolution stage, importance of bacterial colonization) and the most important in term of size; larger ulcers mean more time to close. This difficulties are a common problem in geriatric population and frequently limiting the conclusion of clinical trials in such population.

Conclusion

This double-blind multicenter 2-arm study compared 10g OKG regimen to placebo in the treatment of heel pressure ulcers. The main efficacy criterion was the reduction in ulcer area at week 6. This study supports a potential benefit of a 10g daily dose of OKG in the subgroup of patients with pressure ulcers ≤ 8 cm2 surface area. OKG seems to have a booster effect during the first two weeks, attested by an accelerated closure rate. However this study highlights methodological difficulties to perform clinical trials in old-old patients that may affect the robustness of the results for this type of study.

Acknowledgements: We thank the study investigators for their work in performing the trial. Bulgaria: HARALANOV Sofia, IOTOV Sofia, France: ALIX La Rochelle, BAUDET-SAUCET Lons Le Saunier, BERBER Goussonville, BOCHER Vigneux De Bretagne, CARNEIN Colmar, CONSTANS Tours, COSTES Gonesse, COUTURIER Grenoble, DANIEL Menucourt, DRUNAT Plaisir, DUBUSS Angers, DUJARDIN Roubaix, GEORGE Nancy, GOLDFARB Vannes, GRANGE Albigny sur Saône, GREUILLET Chambery, GRUEL Barbezieux Saint Hilaire, HADDAD Versailles, HAULON Paris, JAMET Hyères, JEANDEL Montpellier, LALU-FRAISSE Dijon, MARC Oissel, MEAUME Ivry sur Seine, MICHEL Nice, NACHAR Avignon, PAILLAUD Créteil, PRADERE Poitiers, RIFAÏ Arras, SALLES Pessac, SALOM Magnanville, SAUVAGE Limoges, SCHATZ Bischwiller, SEBBANE Sevran, SIMON Elbeuf, TAILLANDIER Villejuif, TRUCHETET Thionville, VANNEREAU Nîmes. Germany: KLEIN Künzing, KOWALZICK Plauen, MUENTER Hamburg, NIESCHIK Leipzig, NORGAUER Jena, OSTER Heidelberg. Italia : BERNABEI Fontecchio, CHINNI Roma, FELLER Garbagnate Milanese, FORCONI Siena, MASINA Bentivoglio, ROMANELLI Pisa, SALSI Bologna, SCALISE Ancona, TULLI Chieti. Romania : BOIANGIU Bucuresti, FARCASIU Bucuresti, IANOSI Craiova, PETRESCU Iasi. Spain: ALTUBE Madrid, HIERRO BEGONTE Madrid, CASADO Madrid, CUENLLAS Madrid, MARTINEZ Pinto, MONSALVE Madrid, MORANTE Madrid, OLIVER Valencia, RODRIGUEZ Madrid

Declaration of interest: This study was sponsored by a grant from CHIESI France and Italy.