Efficacy and Safety Study of Dovramilast in People With Leprosy Type 2 Reaction

Официальное название

A 12-week, Open-label, Randomized, Standard of Care Controlled, Dose-ranging Safety and Efficacy Study of Dovramilast in People With Moderate to Severe Acute or Recurrent Leprosy Type 2 Reaction

Обзор

Dovramilast has not been approved for leprosy type 2 reaction (erythema nodosum leprosum, ENL) or any other disease anywhere in the world. In this study, an experimental drug called dovramilast is being tested to see how it compares to current treatments for leprosy type 2 reaction. Specifically, this study aims to assess the efficacy of 100mg or 150 mg dovramilast compared with standard treatments (also known as standard of care). This study also aims to assess the safety of two strengths in adults with leprosy type 2 reaction.

Вмешательства

• Препарат Dovramilast
  Dovramilast
• Препарат Prednisolone
  Standard of care
• Препарат Thalidomide
  Standard of care (US only)

Первичные конечные точки

• The proportion of dovramilast (100 mg or 150 mg) recipients achieving a 75% improvement in leprosy type 2 reaction skin lesions at week 12 [Срок оценки: 12 weeks]
• Incidence and severity of adverse events [Срок оценки: 12 weeks]

Вторичные конечные точки (12)

• Resolution of fever to ≤ Grade 1 [Срок оценки: 12 weeks]
• Skin lesion count changes [Срок оценки: 12 weeks]
• Change from Baseline ENLIST (Erythema Nodosum Leprosum International Study ) severity scale score [Срок оценки: At each post Baseline time point]
• Change from Baseline of each of the following parameters when present at Baseline at Grade 2 or greater [Срок оценки: from baseline to Week 12]
• Changes in neuropathy from Baseline grade [Срок оценки: 12 weeks]
• Time to resolution [Срок оценки: 12 weeks]
• Proportion of subjects requiring Rescue medication and time to initiation of Rescue medication [Срок оценки: 12 weeks]
• Total amount of treatment for leprosy type 2 reaction administered [Срок оценки: 12 weeks]
• Recurrences [Срок оценки: 48 weeks]
• Exposure metrics of dovramilast [Срок оценки: 48 weeks]
• Exposure metrics of the dovramilast metabolite M15 [Срок оценки: 48 weeks]
• Skin lesion count changes [Срок оценки: 12 weeks]

Критерии участия

Критерии включения

• Aged 18 years of age or older.
• Provision of written informed consent.
• Laboratory confirmed previous or current Mycobacterium leprae or Mycobacterium lepromatosis infection.
• Leprosy type 2 reaction meeting the following criteria:

• Either:

i. Acute (first episode and no treatment initiated) or ii. Recurrent (at least one further episode occurring 28 days or more after withdrawal of leprosy type 2 reaction treatment).

• Presence of at least 10 leprosy type 2 reaction tender papular and/or nodular skin lesions (not including scars).
• An ENLIST score of at least 9.
• If a woman of reproductive potential, agree to the use of two reliable contraceptive measures (at least one of which is a highly effective form of contraception) from Screening until at least 4 weeks after completion of treatment with dovramilast or standard of care. Refer to Special Considerations for additional information.
• If male (including those who have had a successful vasectomy), agree to using a latex condom during any sexual contact with women of reproductive potential from Screening until at least 4 weeks after completion of treatment with dovramilast or standard of care.

Критерии исключения

• Chronic leprosy type 2 reaction, defined as the reaction occurring for 24 weeks or more during which a subject has required treatment either continuously or where any treatment free period had been < 28 days.
• Receipt of thalidomide, lenalidomide, pomalidomide, systemic corticosteroids, clofazimine (> 50 mg/day), apremilast or any other phosphodiesterase (PDE) 4 inhibitor, or immunosuppressive/immunomodulatory treatment within 28 days of Baseline.
• Receipt of an investigational agent within 28 days of Baseline or 5 half-lives of the investigational agent (whichever is longer).
• Leprosy type 2 reaction with orchitis, uveitis, iritis, or severe neuritis (Grade 3 or greater severe neuritis).
• Current diagnosis of leprosy type 1 reaction or Lucio's phenomenon.
• Current tuberculosis, malaria, cutaneous or visceral leishmaniasis or other serious bacterial, viral, or parasitic infection at Screening or Baseline.
• Active systemic fungal infection requiring or undergoing treatment.
• Other than leprosy type 2 reaction, any clinically significant (as determined by the Investigator) cardiac, endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic disease, or other major disease that is currently uncontrolled.
• Other than leprosy type 2 reaction, any other dermatological condition that could, in the opinion of the Investigator, interfere with the study assessments.
• Chronic hepatitis B, chronic hepatitis C, or human immunodeficiency virus (HIV) positive.
• Pregnant women or breastfeeding mothers.
• Use (or planned use) of antimetabolites or alkylating agents, rifampin use more frequent than monthly, phenobarbital, carbamazepine, phenytoin, traditional or herbal preparations (including St. John's wort), foods (including grapefruit) known to affect activity of the cytochrome (CYP)3A4 enzyme or use (or planned use) of all strong CYP3A and P-gp inhibitors including ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, ritonavir, cobicistat, diltiazem. Substrates of CYP3A4, CYP2C9, CYP2C19, and P-gp should be used with caution when concomitantly administered with dovramilast.
• Known or suspected active substance abuse or a history of substance abuse within 6 months prior to Screening.
• Prior history of suicide attempt at any time in the subject's lifetime prior to Screening or Randomization, or major psychiatric illness requiring hospitalization within the last 3 years.
• Current diagnosis of depression, and/or history of suicide ideation
• History of or presence of cardiac disease, including:

• Clinically significant abnormal electrocardiogram
• QTcF > 450 msec
• Receipt of a vaccination within 7 days of Baseline.
• Known or suspected hypersensitivity to: PDE4 inhibitors including dovramilast or apremilast; thalidomide; prednisolone, or; excipients used in the formulation of dovramilast, thalidomide or prednisolone.
• Body Mass Index < 15 kg/m\^2 or > 35 kg/m\^2.
• Unable to, or significant difficulty with, swallowing tablets/capsules.
• Anemia requiring transfusion.
• History of or current pancreatitis.
• Known or suspected cirrhosis of the liver.
• The following laboratory abnormalities:

• White blood cells (WBC) < 2.5 x 10\^9/ L.
• Neutrophils (granulocytes) < 1.0 x 10\^9/L.
• Platelets < 80 x 10\^9/L.
• Aspartate aminotransferase or alanine aminotransferase > 2 times the upper limit of reference range.
• Albumin < 30 mg/dL.
• Bilirubin > 2 mg/dL
• Calculated creatinine clearance (Cockcroft Gault) < 50 milliliter (mL)/minute.
• Lipase ≥ 1.6 times the upper limit
• Previous participation in this study
• Unwilling, unlikely or unable to comply with all protocol specified assessments, including photographic assessments
• Enrolled in another leprosy type 2 reaction treatment study

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Harborview Medical Center, University of Washington — Seattle

Benin · 1 центр

• Centre de Dépistage de Traitement de la Lèpre et de l'Ulcère de Burulli — Abomey-Calavi

Côte d’Ivoire · 1 центр

• Chr de Divo — Divo

Индонезия · 1 центр

• Universitas Gadjah Mada — Yogyakarta

Madagascar · 1 центр

• Programme national lutte contre la lèpre — Tôlanaro

Филиппины · 1 центр

• Philippine General Hospital, University of the Philippines, Manila — Manila

Идентификаторы

NCT: NCT07172659 · MDGH-DOV-2001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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