Table 1.
ASO.
| No | Study registration number (ref) | Study Population | Age Group | Intervention Arm | n | Comparator arm | n | Time to follow Up | Primary Endpoint | Outcome: Mean Difference (Treatment vs Placebo) | Adverse Events |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | NCT00216463 (Furtado, 2012) | hypercholesterolemic LDL-C ≥130 mg/dL and TG ≤ 4oomg/dL BMI 25–32kg/m2 |
18–65 years old | Mipomersen once a week. Doses 100 mg 200 mg 300 mg For a total of 13 weeks |
8 8 6 (apoCIΩ |
Placebo | 2 2 2 |
Day 99 | Total cholesterol; Concentration of ApoCIII; concentration of apoB |
Total Cholesterol 100 mg = −33.3 (−60.6, −5.9) p = 0.004 200 mg = −78.4 (−105.7, −51.1) p < 0.001 300 mg = −108.5 (−136.9, −81.0) p < 0.001 ApoB 100 mg = −30.3 (−46.2, −14.3) p = 0.001 200 mg = −57.3 (−72.3, −42.3) p < 0.001 300 mg = −84.5 (−100.3, −68.7) p < 0.001 ApoCIII 100 mg = 0.97 (−3.1, 5.1) p = 0.6 200 mg = −5.81 (−10.1, −1.5) p = 0.01 300 mg = −6.03 (−8.9, −3.2) p < 0.001 |
Not reported |
| 2 |
NCT02160899 NCT02414594 (Viney, 2016) |
64 participants to the phase 2 trial (35 in IONIS-APO(a)Rx and 29 in placebo in June 25, 2014, to Nov 18, 2015). 58 healthy volunteers to the phase 1/2a trial of IONIS-APO(a)-LRx (28 in sd group and 30 in md group in April 15, 2015, to Jan 11, 2016) | Adult | A: IONIS-APO(a)Rx 100 mg SC, once a week for 4 weeks, 200 mg SC, once a week for 4 weeks, then 300 mg SC, once a week for 4 weeks B: IONIS-APO(a)-LRx 6 doses of 10 mg, 20 mg, or 40 mg at days 1, 3, 5, 8, 15, and 22, for a total dose exposure in the active arms of 60 mg, 120 mg, or 240 mg per cohort |
A: 51 B: 13 |
Placebo | A: 26 B: 3 |
A: day 85 or 99 B: day 30 |
A: reduction of Lp(a) plasma concentration B: reduction of Lp(a) plasma concentration |
A: 66.8% (61.6, 72) B: 24·8% (3·1, 67·1) for 10 mg, 35·1% (2·2, 8·8) for 20 mg, 48·2% (10·9, 78·4) for 40 mg, 82·5% (50·5, 109·2) for 80 mg, 84·5% (65·2, 112·6) for 120 mg |
There were two serious adverse events (myocardial infarctions) in the IONIS-APO(a)Rx phase 2 trial, one in the IONIS-APO(a)Rx and one in the placebo group, but neither were thought to be treatment related. 12% of injections with IONIS-APO(a)Rx were associated with injection-site reactions. IONIS-APO(a)-LRx was associated with no injection-site reactions. |
| 3 | European Clinical Trial Database 2012-004909-27 (Tsimikas et al., 2015) | healthy adults, BMI less than 32•0 kg/m(2), Lp(a) 25 nmol/L (100 mg/L) or more | 18–65 years old | ISIS-APO(a)Rx, Single dose, SC injection 50 mg 100 mg 200 mg 400 mg ISIS-APO(a)Rx, Multi dose, SC injection 100 mg for a total dose exposure of 600 mg 200 mg for a total dose exposure of 1200 mg 300 mg for a total dose exposure of 1800 mg |
3 3 3 3 8 8 8 7 |
Placebo | Single dose: 4 Multi dose: 6 |
day 30 day 36 |
Lp(A) reduction | Single doses of ISIS-APO(a)Rx (50–400 mg) did not decrease Lp(a) concentrations at day 30. Placebo outcome change from baseline: 5% (−8,15) Multidose ISIS-APO(a)Rx 100 mg 39.6%, p = 0.005 200 mg 59.0%, p = 0.001 300 mg 77.8%, p = 0.001 |
Mild injection site reactions were the most common adverse events. 2 volunteers excluded due to AE (one each in ISIS-APO(a)Rx 200 mg md (ec injection site adverse event) and 300 mg md (ec flu-like syndrome that resolved without sequelae). No SAE. Mild injection site reactions were the most common adverse events. ≥10% of participant in ISIS-APO(a)Rx group got headache and fatigue, no significantly different compared to Placebo. |
| 4 | Waldman, E (2017) | Established atherosclerosis, LDL ≥ 3.4 mmol/L (130 mg/dL) despite on stable maximal possible lipid lowering therapy for more than ≥ 3 months, BMI ≤ 40 kg/m2, women had to be postmenopausal or on highly effective contraceptive regimen, and fulfilled German criteria for lipoprotein apheresis | >18 yo, mean 42-72 yo | Mipomersen 200 mg, SC injection, weekly for 26 weeks (at least 12 weaks) | 11 | none | 4 | 26 weeks, or between 12 and 26 weeks for discontinued patients (n = 4) | pre apheresis LDL cholesterol | −0.02 (−1.1, 1.1) p = 0.002 | Of the 11 patients randomized to mipomersen, 3 discontinued the drug early due to side effects (2 for injection site reactions and 1 for flu-like symptoms) and were replaced. Further 4 patients discontinued mipomersen during treatment weeks 12e26, again for side effects (1 due to elevations of liver enzymes, the other 3 due to moderate to rather severe injection site reactions (ISR) and flu-like symptoms (FLS)) and were not replaced. |
| 5 | NCT01713361 (Büller et al., 2015) | undergoing elective primary unilateral total knee arthroplasty | 18–80 years old | FXI-ASO, SC injection 200 mg 300 mg 9 times at day 1,3,5,8,15,22,29,36,39 |
134 71 |
enoxaparin 40 mg | 69 | 3 months | Incidence of adjudicated total thromboembolism which was a composite of asymptomatic DVT, objectively confirmed symptomatic venous thromboemolism, fatal PE, unexplained death which PE could not be ruled out. | Efficacy (Total Venous Thromboembolism) 200 mg = −15 (−37, 7) p = 0.59 300 mg = −18 (−16, −29) p < 0.001 |
Total 12 AE (bleeding), 6 of which related to treatment. |
| 6 | Dasgupta et al. (2019) | Biopsy proven ATTR amyloidosis (hereditary or wild type) with clinical signs and symptoms of CHF (NYHA I - III), a left ventricular wall thickness ≥ 1.3 cm on TEE, stable renal function (GFR >35) and stable thyroid function (TSH <10 or normal serum T4) | No age restriction (mean 63.4–76.2 years old) | Inotersen 300 mg/1.5 ml subcutaneous/week |
33 | None | None | Every 6 months, MRI every year if there is no contraindication Still ongoing (3 years by the time this journal was published) |
Decrease of LV mass (MRI), Decrease in left ventricular septal thickness (TEE), Increase of exercise tolerance (6MWT), Stable LVEF, Steady decline of BNP. | Total 8 AE, all related to treatment. AEs: Inflamation & Induration on the site of injection |
|
| 7 | NCT01713361 (Tsimikas et al., 2020) | elevated screening plasma lipoprotein(a) level (≥60 mg per deciliter [150 nmol per liter]). Confounding factors: CAD, Overweigh, HT, DMT2, Familial Hypercholesterolemia, smoking |
Adult 18–80 years old | APO(a)-LRx, SC injection 20 mg every 4 weeks, 40 mg every 4 weeks, 60 mg every 4 weeks, 20 mg every 2 weeks for 6 months |
48, 48, 47, 48, 48 |
Placebo normal saline per week | 47 | 6 months | percent change in Lipo(a) at 6 monts exposure, safety and efficacy | 20 mg/4 weeks = 80.7 (1.2, 21) p = 0.003; 40 mg/4 weeks = 101.7 (7.3, 131.4) p < 0.001; 20 mg/2 weeks = 115.1 (9.8, 195) p < 0.001; 60 mg/4 weeks = 134.3 (24, 627.4) p < 0.001; 20 mg/1 weeks = 172.6 (109.3, 11.571)p < 0.001 |
Total 253 AE, 212 of which related to treatment. 2 deaths due to traffic accident and suicide. AEs:. influenza like symptoms, injection site reaction |
| 8 | Santos, Raul D (2015) | HoFH, Severe-HC, HeFH-CAD, HC-CHD | ≥ 12 years old | Mipomersen 200 mg, SC injection, weekly for 26 weeks | Total 261 HoFH 51, Severe-HC 58, HeFH-CAD 124, HC-CHD 157 |
placebo | 129 | week 28 - week 28 + 24 | LDL-C | HoFH = 0.3 (0.04, 0.6), p = 0.002; Severe-HC = 0.6 (0.4, 0.8) p = 0.002; HeFH-CAD = 0 (−0.2, 0.2) p = 0.001; HC-CHD = 0.6 (0.4, 0.8) p < 0.001 |
injection site reaction (+). |
| 9 |
NCT00607373 NCT00706849 NCT00770146 NCT00794664. (Raal et al., 2010, Stein et al., 2012, Mcgowan et al., 2012) |
HoFH, Severe-HC, HeFH-CAD, HC-CHD Comorbidites: smoker, metabolic syndrome, overweight-obese |
n/a | Mipomersen 200 mg, SC injection, weekly for 26 weeks | 382 HoFH 51, Severe-HC 57, HeFH-CAD123, HC-CHD 151, |
placebo | 126 | week 28 | Lp(a) | −26.4 (−32.1, −20.7) p < 0.001 median (interquartile range) | |
| 10 | NCT00770146 (thomas et al., 2013) | HC, CHD Comorbidities: DMT2 |
≥18 years old | Mipomersen 200 mg SC injection weekly, for 28 weeks | 101 | placebo | 50 | week 28 - week 24 | LDL-C | −38 (−49.3824, −26.6176) p < 0.001 | A total of 139 patietns experiencing AEs, 97 of which related to treatment. AEs: injectio site reaction, flu-like symptoms, ALD increased, hepatic stetosis |
| 11 | Luigetti, M et al. (2022) | hereditary aTTR | n/a | inotersen 14.6 ± 5.9 months (range, 6–24 months) | 23 | none | none | 6–14.6 months | troponin, NTpro BNP, intervent septum thickness, BMI safety-- > number of dropouts |
Troponin 0.01 (−0.0052, 0.0252) p = 0.19; NTpro BNP -45.6 (−703.82, 612.62) p = 0.88 IVS 1.5 (−0.46, 3.46) p = 0.12 |
5 dropouts, 2 of which related to treatment. 20 AEs are all related to treatment, which are: 4: severe thrombocytopenia 9: mid trombocytopenia 7: mild thrombocytopenia |
| 12 | Yang, X et al. (2016) | hyperTAG cohort 1: FCS cohort 2: hyperTAG of varying causes cohort 3: stable fibrate therapy |
adult | Volanesorsen 100 mg, 200 mg, 300 mg weekly for 13 weeks |
11, 13, 11 |
Placebo | 16 | 176 days | apoCIII-apoB | apoCIII-ApoB 100 mg −31 (−17005, 16943) apoCIII-ApoB 200 mg 21026 (8505, 33547) p < 0.001 apoCIII-ApoB 300 mg −626803 (−640678, −612928) p < 0.001 |
not reported |
| 13 | Benson, MD et al. (2017) | hereditary and wild-type ATTR with moderate-severe cardiomyopathy biopsy-proven |
adult/elderly >55 years old | IONIS-TTR]) | 10 patients experiencing AEs | ||||||
| 14 | Reeskamp, L et al. (2018) | high risk and severe HeFH persistent hyperchol maximal LDL-lowering therapy Comorbidities: Smoking Alcohol consumption HoFH CHD other atherosclerotic disease Hypertension DM statin |
Adult>18 years old | Mimopersen 200 mg SQ 1x/week 70 mg SQ 3x/week for 60 weeks |
104 102 |
Placebo | 57 25 |
84 weeks | percent change LDL | −20.96 (−29.5085, −12.4115) p < 0.001 −18.80 (−20.7270, −16.8730) p < 0.001 |
A total of 259 AEs, 178 of which related to treatment |
| 15 | Sugihara, C et al. (2015) | dual chamber PPM and AF burden 1-10 comorbidities: Use of dabigatran/warfarin HT DM Hyperlipidemia Hypothyroidism Prior stroke Use of card meds as indicated above |
adult >18 years old | ISIS-CRPRx 200 mg in 1 mL solution/SC in two injection 3x/wk for 1 week 1x/wk for 3 wks Total intervention: 4 weeks |
7 | none | none | every visit during drug administration; 4 week; and 8 week |
change in AF burden before and after | MD: 1.6% (−1.45% to 4.65%) p = 0.37 CRP: -2.9 (−5.95, 0.15) mg/L p = 0.031 |
|
| 16 | NCT03728634 (Viney et al., 2020) | healthy, non-pregnant,/lactating, BMI <32, able to take vitamin A | 18–65 years old | AKCEA-TTR-LRx (ION-682884)120 mg SD/SC 45 mg 4x dose/SC, 1x/month for 4 months 60 mg 4x dose/SC, 1x/month for 4 months 90 mg 4x dose/SC, 1x/month for 4 months |
9 10 10 10 |
placebo | 2 2 2 2 |
safety assesment: AEs-- > physical and lab findings PK parameters PD parameters |
TTR SD: -80.40 (−94.0 to −66.8) 45 mg: -79.80 (−95 to −64.6), p < 0.001 60 mg: -84.60 (−98.9 to −70.3), p < 0.001 90 mg: -87.90 (−97.4 to −78.4), p < 0.001 |
A total of 7 AEs, 6 of which related to treatment. | |
| 17 | NCT01737398 (Benson et al., 2018) | stage 1 and 2 hereditary TTR amyloidosis comorbidites: Val30Met TTR mutation stage 1 vs stage 2 Previous treatment with tafamidis and diflusinal |
adults | inotersen 300 mg, SC injection, 3 injection for the 1st week, followed by weekly injection up to 65 wks (67 doses) | 87 | placebo | 52 | 1 week after initiation 35 wks after initiation 66 week post treatment |
“mNIS+7 score Norfolk QOLD-DN score" |
mNIS+7: -19.70 (−21.3 to −18.1) p < 0.001 norfolk QOL-DN: -.17(xxxxx) p < 0.001 |
A total of 199 AEs, 119 of which related to treatment. 110→ any AEs 9→ serious AEs. |