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A multicenter, open-label, single-arm study of a TRPV2 inhibitor against cardiomyopathy of muscular dystrophy (Tranilast-MD)

Tranilast-MD (Tranilast-MD)

18

Patients with advanced stage heart failure muscular dystrophy with BNP>=100 pg/mL who had not responded adequately to standard myocardial protection therapy were included. Study treatment was initiated in 18 patients with a median age of 32.5 years (interquartile range: 27-41 years). 16 patients (88.9%) were male. The disease types were DMD in 13 patients, dystrophin abnormalities in 3, and LGMD in 2. The median BNP before treatment initiation was 178.0 pg/mL (interquartile range: 126-260 pg/mL).

For the subjects in this study were patients with advanced heart failure and in poor general condition, we performed 36 screening tests on 34 subjects, but only 28 subjects were enrolled, and a large number of subjects dropped out before treatment implementation, resulting in that only 18 subjects were received the study treatment. 6 patients discontinued study treatment, 12 patients completed 144 weeks, 18 patients underwent safety analysis, 17 patients achieved FAS, and 13 patients completed PPS (primary endpoint).

Serious adverse events occurred in 8 cases during the study period. A summary is given below. Case 1 was a case of septic shock due to exacerbation of a pre-existing respiratory infection and died 39 days after starting of the study treatment; the SAE committee determined that a causal relationship to the study drug was deniable. Case 15 was treated with intravenous drugs for 139 weeks for congestive heart failure triggered by pneumonia, and the SAE Committee concluded that a causal relationship to the study drug could be ruled out. Case 16 showed that BNP (mean 338 pg/mL pre-dose, 213 pg/mL 4 weeks post-dose, 169 pg/mL 12 weeks post-dose) and hANP (279 pg/mL pre-dose, 257 pg/mL 4 weeks post-dose, 170 pg/mL 12 weeks post-dose) declined after the study treatment, while cystatin C increased (1.05mg/L pre-dose, 1.84mg/L 4 weeks post-dose, 2.8mg/L 12 weeks post-dose). When we had reduced Tranilast to 200 mg/day from 16 weeks, LVDd reduced from 61 mm to 47 mm at 20 weeks, BNP and cystatin C increased to 190 pg/mL and 3.18 mg/L, respectively. Since we had performed Selara induction and Luprac dose increase (from 2 mg/day to 4 mg/day) in this patient 4 weeks prior to the start of study treatment, the case was judged to have decreased circulating blood volume due to diuretics and renal dysfunction due to ACEI. When we implemented Renivace reduction (from 10 mg/day to 5 mg/day) and diuretic reduction (discontinuation of Selara and Luprac from 4 mg/day to 2 mg/day), the case improved to cystatin C 1.93 mg/L in a few days. The SAE committee determined that a causal relationship with the study drug could be ruled out. Case 18 developed appendicitis at 35 weeks, and the SAE Committee concluded that a causal relationship to the study treatment could be ruled out. In Case 19, diarrhea appeared on the 10th day after starting study treatment, and administration of the study drug was discontinued on the 13th day. The symptoms improved and the patient resumed treatment on the 21st day, but diarrhea recurred on the 25th day and the study drug was discontinued. The patient resumed treatment on the 32nd day, but was hospitalized on the 33rd day due to dehydration and decreased blood pressure, which improved with intravenous fluids. Diarrhea is listed in the package insert as a side effect of less than 0.1-5% of the test drug, and since the timing of the symptoms coincided with oral administration, it was determined that it was an adverse event caused by the test drug, and the test treatment was discontinued. Case 20 was admitted to the hospital at 45 weeks with arrhythmia due to electrolyte abnormalities caused by summer fatigue. The SAE committee concluded that a causal relationship to the study drug could be ruled out. Case 20 developed symptoms of heart failure after taking oral NSAIDs for hip pain at 100 weeks and was hospitalized with intravenous administration of a diuretic and vasopressor. The SAE committee determined that a causal relationship to the study drug could be ruled out. Case 24 died of aspiration pneumonia at week 112; the SAE committee determined that there was no causal relationship to study treatment. Case 28 had a gastrostomy at 75 weeks due to progressive dysphagia, and the SAE committee concluded that a causal relationship to the study drug could be ruled out. The patient continued to suffer from insomnia after gastrostomy, and an increase in BNP was observed at 86 weeks. The SAE committee concluded that a causal relationship to the study drug could be ruled out. Furthermore, patient suffered cardiac arrest due to asphyxia at 94 weeks, and although he was resuscitated, he did not recover and died at 97 weeks.

Results of efficacy evaluation: Primary endpoint: BNP (3-1 BNP) In the FAS, GM+/-GSD before treatment initiation was 192.9+/-1.72, median 185.0, IQR 132-260, range 94-568; mean GM+/-GSD at 20, 24and 28 weeks after treatment initiation or at discontinuation up to 20 weeks after treatment initiation was 188.8+/-1.92, median 199.0, IQR 101-351, range 55-493. The change from baseline was -2.1 (95% CI -21.5, 22.0) and -4.3% (95% CI -20.8, 15.6) in the mixed effects models (fixed effects: time point, random effects: subjects), and the t-test (H0: log(u_24)-log(u_0) = 0.18) for the change from before administration after log transformation had a p value of 0.071 (the null hypothesis of 0.18 is approximately log(1.197) that is equivalent to a rate of change of 19.7%). The mean BNP change during the study period has been generally below the baseline until week 48, and although GM exceeded baseline after 72 weeks, the 95% CI did not include 0 only at 144 weeks. Secondary Endpoints: 1) Internal diameter shortening rate of left ventricular (4-2-3 FS) Mean+/-SD in the FAS (17 cases) was 9.02+/-3.83% median 8.90%, IQR 6.0-12.5%, range 3.0-14.0%. After 24 weeks (15 cases), mean+/-SD was 9.24+/-4.06% median 9.00%, IQR 6.0-12.5%, range 1.0-15.0%. Change (15 cases) was mean+/-SD 0.22+/-0.98%, median 0.00, IQR -0.2-0.8%, range -2.0-2.0%, 95%CI -0.32-0.76%, p=0.401. During the long-term treatment period, the mean FS tended to increase until 72 weeks, then gradually has decreased until 144 weeks, when it returned to the baseline value. 2) hANP, cTnT (4-2-7 hANP cTnT CK) For hANP, GM+/-GSD in the FAS before starting (17 cases) was 189.7+/-1.74, median 223.0pg/mL, IQR 152-284pg/mL, range 77-378pg/mL. After 24 weeks or at discontinuation (17 cases), GM+/-GSD was 199.1+/-2.19, median 257.0 pg/mL, IQR 123-380 pg/mL, range 44-515 pg/mL with the change rate of 5.0%, point estimate (95% CI) -13.6-27.6%, p=0.605. In the long-term treatment period, the rate of change was >10% after 72 weeks, but the 95% CI included 0 throughout the entire period. For cTnT, GM+/-GSD in the FAS before the start of administration (17 cases) was 0.026+/-1.76, median 0.024ng/mL, IQR 0.02-0.03ng/mL, range 0.01-0.08ng/mL. Four weeks after administration, GM+/-GSD was 0.030+/-1.79, an increase of 12.5%, and 24 weeks after administration or at the time of discontinuation (17 cases), GM+/-GSD was 0.030+/-1.88, median 0.022ng/mL, IQR 0.02-0.05ng/ mL, range 0.01-0.14ng/mL, the rate change of 14.6%, point estimate (95% CI) 1.1-29.9%, and p=0.035. cTnT after 4 weeks remained stable during the long-term treatment period, and the 95% CI included 0 throughout the period. 3) Peripheral blood mononuclear cell surface TRPV2 expression (4-2-4 TRPV2express) Mean+/-SD in the FAS before treatment (17 cases) was 30.67+/-10.11%, median 26.98%, IQR 24.4-33.9%, and range 16.2-49.4%. After 4 weeks of treatment (17 cases), mean+/-SD was 9.91+/-9.51% median 7.20%, IQR 4.6-12.7%, and range 0.6-35.8%. The change was mean+/-SD -20.76+/-16.74%, median -21.22%, IQR -29.4 to -15.0%, range -46.7 to -19.6%, 95%CI -29.37 to -12.15%, p<0.001. After 12 weeks, the number of patients measured was limited due to effort items but remained low throughout the study period. 4) Muscle strength (hand pinch strength) and creatine kinase (4-2-5 hand pinch strength, 4-2-7 hANP cTnT CK) For hand pinch strength, mean+/-SD in the FAS before treatment (17 cases) was 1.00+/-1.74kg median 0.4kg, IQR 0.2-0.8kg, range 0.1-6.3kg. After 24 weeks of treatment (15 cases), mean+/-SD was 0.78+/-1.28kg median 30kg IQR 0.1-0.7kg, range 0.1-4.8kg. The change (15 cases) was mean+/-SD -0.29+/-0.98kg, median 0.00, IQR -0.2-0.1, range -3.8 - 0.1, 95%CI -0.83-0.25, p=0.269. No significant changes were observed during the long-term treatment period. For creatine kinase, GM+/-GSD in FAS before starting (17 cases) was 269+/-2.12, median 221 IU/L, IQR 157-382 IU/L, range 88-1996 IU/L. GM+/-GSD after 24 weeks of treatment or at discontinuation (17 cases) was 278+/-2.41, median 279 IU/L, IQR 169 - 1668 IU/L, range 31-1668 IU/L with a change of 3.5%, point estimate (95%CI) -.0 - 3.0 median 279 IU/L, IQR 169-1668 IU/L, range 31-1668 IU/L with a change of 3.5%, point estimate (95% CI) -23.0 - 39.2%, p=0.808. GM during the long-term treatment period remained lower than baseline, but 95%CI included 0 throughout the entire period. 5) MDQOL-60, SF-12 (4-2-6 QOL) MDQOL-60 is a quality-of-life assessment scale for muscular dystrophy and related disorders developed by Kawai, et al. It consists of 60 questions in 11 areas. The 11 areas are 1. psychological stability, 2.ADL, 3. environment, 4. hope, 5. activity, 6. health, 7. human relationships, 8. family, 9. sexuality, 10. respiration and pharyngeal function, and 11. defecation. There was no significant difference (p<0.05) in the amount of change in the FAS, but there was a trend toward improvement in sex (15 cases) at 24 weeks with mean+/-SD 9.4+/-17.2, median 16.6, IQR 0-25, range -25-33, 95%CI -0.1-19.0, p=0.052. At 48 weeks of treatment, the rate improved to 14.7+/-19.9 95%CI 2.7-26.8, but thereafter there was no significant difference. In SF-12, of the physical, mental, and role/social summary scores, the amount of change (14 cases) decreased the role/social summary score to mean+/-SD -11.4+/-16.8, median -13.5, IQR -24-1, range -35-25, 95%CI -20.7 to -1.3 at 24 weeks, p=0 .029, but then returned to around the baseline value. Among the subscales, daily role function (mental) decreased mean+/-SD -9.7+/-14.1, median -6.1, IQR -12-0, range -49-6, 95%CI -17.5 to -1.9, p=0.018, but returned to baseline values in the long-term treatment period.

Although there was no significant improvement in cardiac function, BNP, hANP, left ventricular fractional shortening, and other cardiac indices were maintained throughout the study period despite the advanced disease. Furthermore, no cardiac deaths were observed, and the 144-week survival rate exceeded 80%. TRPV2 expression on the surface of peripheral mononuclear cells was markedly suppressed after treatment.

Jan. 09, 2025

Jan. 09, 2025

https://ojrd.biomedcentral.com/articles/10.1186/s13023-025-03538-1

No

No

https://jrct.mhlw.go.jp/latest-detail/jRCTs031180038

Matsumura Tsuyoshi

National Hospital Organization OsakaToneyama Medical Center

5-1-1 Toneyama, Toyonaka, Osaka, Japan

tmatsumura-toneyama@umin.org

Ito Yutaka

National Hospital Organization Nagoya Medical Center

4-1-1 Sannomaru, Naka-ku, Nagoya, Aichi, Japan

+81-52-951-1111

study.office@nnh.go.jp

Complete

Oct. 01, 2018

Interventional

single arm study

open(masking not used)

no treatment control/standard of care control

single assignment

treatment purpose

1) MD patients aged 13 or more
2) With high value in BNP (100 pg/mL or more)
3) Those introduced with standard myocardium protective drugs (angiotensin converting enzyme inhibitor (ACEI)/angiotensin type II receptor blocker (ARB) and/or beta blocker) who meets both of the following:
taking maintenance doses at the time of consent;
whose dosage regimen and doses are fixed from 2 weeks before the start of administration until the start of administration.
4) To whom intrinsic administration of capsule, fine granules or dry syrup is possible, or who can be reliably administered tranilast by tube
5) Provided written consent by their free will / the representative

1) Acute stage heart failure condition (using cardiotonic, diuretic, antiarrhythmic drug intravenously)
2) From 2 weeks before the start of administration to the start of administration Directions of digitalis, diuretic, aldosterone antagonist, cardiotonic agent, antiarrhythmic drug are not fixed
3) With a lethal arrhythmia including ventricular premature contraction of more than four (short run)), excluding those with transplanted implantable defibrillators
4) With serious renal dysfunction (estimated glomerular filtration ratio (eGFR) using cystatin C of less than 30 mL/min/1.73 m2)
Male: eGFR = (104 ^ Cystatin C-1.019^ 0.996age (years)) - 8
Female: eGFR = (104 ^ Cystatin C-1.019 ^ 0.996age (years) ^ 0.929) - 8
For those aged 18 or less, cyctain C of 2.5 mg/L or more is used.
5) With severe liver function disorder (T. Bil of 10 mg/dl or more, AST and ALT of 500 IU/L or more, ALP of 5 times or more of the normal upper limit, PT of 40% or less, bleeding tendency, hepatic failure symptoms (fulminant hepatitis), cirrhosis of the liver, liver tumor, jaundice prolonged for more than 6 months) (equivalent to grade 3 in "Classification criteria for severity of adverse drug reactions" )
6) Marked white blood cell (WBC) decrease (less than 3000/mm^3), platelet (Plt) decrease (less than 80,000/mm^3)
7) Having a history of hypersensitivity to tranilast
8) Pregnant or possibly pregnant
9) For whom the principal investigator/sub-investigators judged not appropriate for participation in this study

Both

muscular dystrophy

Tranilast 300 mg / day is administered three times per minute.
Treatment for 28 weeks (in principle, outpatient administration). As of the 28th week, reconfirmation of consent regarding continuation of administration is confirmed, and if confirmation is obtained, further treatment for 116 weeks is carried out.

muscular dystrophy ,heart failure ,tranilast

muscular dystrophies

The change in BNP before the start of administration (using the average of values in the pre-treatment observation period and at the start of administration) to 24 weeks (using the average of values at 20 weeks, 24 weeks and 28 weeks)

1) Cardiac events (change of oral medicine for cardiac failure due to cardiac function exacerbation (ACEI/ARB, Beta blocker, digitalis, diuretic, aldosterone antagonist, cardiotonic agent or antiarrhythmic agent), administration of intravenous drugs (cardiotonic agents, diuretics or antiarrhythmic agent), hospitalization due to heart failure or prolongation of hospitalization)
2) All deaths
3) Left ventricula fractional shortening (FS)
4) Human atrial natriuretic peptide (hANP), cardiac troponin T (cTnT)
5) The expression of transient receptor potential cation channel, subfamily V, member 2 (TRPV2) expression on cytoplasminc membrane of isolated peripheral blood mononuclear cells (PBMCs)
6) Hand finger muscle strength (pinch strength), creatine kinase (CK)
7) Muscular dystrophy quality of life-60 (MDQOL-60), The short form (12) health survey (SF-12)
8) Adverse events

+81-52-951-1111

Oct. 23, 2018

None