Metformin for Premature Infants With Bronchopulmonary Dysplasia

Официальное название

A Phase 0/Phase 1 Trial of Metformin for Premature Infants With Bronchopulmonary Dysplasia

Обзор

The overall objective of this study is to investigate the role of metformin in decreasing lung injury and promoting lung growth in premature infants. There are two phases to this pilot study. For Phase 0, the goal is to investigate the safety and tolerance of oral metformin in premature who have been diagnosed with bronchopulmonary dysplasia (BPD) at 36-44 weeks gestation. For Phase 1, the goal is to investigate metformin safety and tolerance in extremely premature infants who are 7-30 days old who have an increased risk of BPD. The main questions it aims to answer are: * how well do older premature infants tolerate metformin? * how well do younger premature infants tolerate metformin?

Подробное описание

In Phase 0, there are four groups with different doses of metformin, starting at 5mg/kg/day to a maximum of 25mg/kg/day. Participants will take oral metformin twice a day for 3, 7 or 14 days, depending on which group they are in. In Phase 1, there are four groups with different doses of metformin, starting at 15mg/kg/day to a maximum of 25mg/kg/day. Participants will take oral metformin once a day for 3, 7, or 14 days, depending on what group they are in.

Вмешательства

• Препарат Metformin (open-label)
  Enteric metformin 5mg/kg/day in two divided doses will be given for three days to two subjects
• Препарат Metformin (open-label)
  Enteric metformin 10mg/kg/day in two divided doses will be given for three days to two subjects.
• Препарат Metformin (open-label)
  Enteric metformin 20mg/kg/day in two divided doses will be given for seven days to three subjects.
• Препарат Metformin (open-label)
  Enteric metformin 25mg/kg/day in two divided doses will be given for 14 days to three subjects.
• Препарат Metformin (open-label)
  Enteric metformin 15mg/kg/day in a single daily dose will be given for three days to 3-6 subjects. Depending on tolerance, the next Cohort will increase to 25mg/kg/day (Cohort 2) or decrease to 10mg/kg/day (Cohort 3)
• Препарат Metformin (open-label)
  Enteric metformin 25mg/kg/day in a single daily dose will be given for three days to 3-6 subjects. Depending on tolerance, either 25mg/kg/day or 15mg/kg/day will be dose selected for the next Cohort (Cohort 4)
• Препарат Metformin (open-label)
  Enteric metformin 10mg/kg/day in a single daily dose will be given for three days to 3-6 subjects. Depending on tolerance, either 10mg/kg/day dose selected for the next Cohort (Cohort 4) or the study will be stopped due to excessive toxicity.
• Препарат Metformin (open-label)
  The dose for this cohort will be selected from either Cohort 2 or 3 based on tolerance. Enteric metformin 10-25mg/kg/day in a single daily dose will be given for seven days to 6 subjects.
• Препарат Metformin (open-label)
  The dose for this cohort will be the same as Cohort 4. Enteric metformin 10-25mg/kg/day in a single daily dose will be given for 14 days to 6 subjects.

Первичные конечные точки

• Number of participants who tolerate metformin [Срок оценки: 14 days after administration of the first dose of metformin]
• Number of participants with treatment-related adverse events [Срок оценки: 14 days after administration of the first dose of metformin]
• Number of participants with treatment-related metabolic acidosis [Срок оценки: 14 days after administration of the first dose of metformin]
• Number of subjects with treatment-related feeding problems [Срок оценки: 14 days after administration of the first dose of metformin]
• Number of subjects who require dose adjustments of metformin [Срок оценки: 14 days after administration of the first dose of metformin]
• Number of subjects with respiratory deterioration [Срок оценки: 14 days after administration of the first dose of metformin]
• Number of subjects who complete pharmacokinetic evaluation of metformin [Срок оценки: 14 days after administration of the first dose of metformin]
• Pharmacokinetic analysis of metformin [Срок оценки: 14 days after administration of the first dose of metformin]
• Number of subjects who complete the treatment protocol [Срок оценки: 14 days after administration of the first dose of metformin]

Вторичные конечные точки (5)

• Incidence of bronchopulmonary dysplasia [Срок оценки: 14 days after administration of the first dose of metformin]
• Incidence of necrotizing enterocolitis [Срок оценки: 14 days after administration of the first dose of metformin]
• Incidence of retinopathy of prematurity [Срок оценки: 14 days after administration of the first dose of metformin]
• Incidence of intraventricular hemorrhage [Срок оценки: 14 days after administration of the first dose of metformin]
• Incidence of patent ductus arteriosus [Срок оценки: 14 days after administration of the first dose of metformin]

Критерии участия

Inclusion Criteria Phase 0:

• Birth gestational age of < 29 weeks AND
• Postnatal age between 8 and 22 weeks AND
• Diagnosed with BPD at 36 weeks postnatal age

Inclusion Criteria Phase 1:

• Birth gestational age of < 29 weeks, AND
• Requiring mechanical ventilation or positive pressure support at 7 days postnatal age, AND
• Postnatal age between 7 and 30 days

Критерии исключения

• Persistent hypoglycemia
• Lactic acidosis
• Feeding intolerance
• Renal or hepatic dysfunction
• Active infection
• Congenital anomalies that preclude feedings
• Infants whose parents have chosen palliative care

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

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Фундаментальное исследование

Центры проведения

США · 1 центр

• Children's Wisconsin — Milwaukee

Публикации

• Rana U, Joshi C, Whitney E, Afolayan A, Dowell J, Teng RJ, Konduri GG. Decreased Liver Kinase B1 Expression and Impaired Angiogenesis in a Murine Model of Bronchopulmonary Dysplasia. Am J Respir Cell Mol Biol. 2024 Oct;71(4):481-494. doi: 10.1165/rcmb.2024-0037OC. PMID 38869353
• Alemon-Medina R, Altamirano-Bustamante N, Lugo-Goytia G, Garcia-Alvarez R, Rivera-Espinosa L, Torres-Espindola LM, Chavez-Pacheco JL, Juarez-Olguin H, Gomez-Garduno J, Flores-Perez C, Fernandez-Perez PG. Comparative Bioavailability and Pharmacokinetics Between the Solid Form of Metformin vs a Novel Liquid Extemporaneous Formulation in Children. Dose Response. 2021 Sep 27;19(3):15593258211033140. d PMID 34602916
• Kirkpatrick EC, Mitchell ME, Thilly WG, Cava J, Tomita-Mitchell A, Gostjeva EV. Use of Metformin in Pulmonary Vein Stenosis after TAPVR Repair. Glob Pediatr Health. 2020 Sep 25;7:2333794X20958924. doi: 10.1177/2333794X20958924. eCollection 2020. No abstract available. PMID 33029553
• Ayoub R, Ruddy RM, Cox E, Oyefiade A, Derkach D, Laughlin S, Ades-Aron B, Shirzadi Z, Fieremans E, MacIntosh BJ, de Medeiros CB, Skocic J, Bouffet E, Miller FD, Morshead CM, Mabbott DJ. Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin. Nat Med. 2020 Aug;26(8):1285-1294. doi: 10.1038/s41591-020-0985-2. Epub 2020 Jul 27. PMID 32719487
• Biag HMB, Potter LA, Wilkins V, Afzal S, Rosvall A, Salcedo-Arellano MJ, Rajaratnam A, Manzano-Nunez R, Schneider A, Tassone F, Rivera SM, Hagerman RJ. Metformin treatment in young children with fragile X syndrome. Mol Genet Genomic Med. 2019 Nov;7(11):e956. doi: 10.1002/mgg3.956. Epub 2019 Sep 14. PMID 31520524
• Brittain EL, Niswender K, Agrawal V, Chen X, Fan R, Pugh ME, Rice TW, Robbins IM, Song H, Thompson C, Ye F, Yu C, Zhu H, West J, Newman JH, Hemnes AR. Mechanistic Phase II Clinical Trial of Metformin in Pulmonary Arterial Hypertension. J Am Heart Assoc. 2020 Nov 17;9(22):e018349. doi: 10.1161/JAHA.120.018349. Epub 2020 Nov 10. PMID 33167773
• Liao S, Li D, Hui Z, McLachlan CS, Zhang Y. Metformin added to bosentan therapy in patients with pulmonary arterial hypertension associated with congenital heart defects: a pilot study. ERJ Open Res. 2018 Aug 22;4(3):00060-2018. doi: 10.1183/23120541.00060-2018. eCollection 2018 Jul. PMID 30151369
• Wang X, Liu Y, Han D, Zhong J, Yang C, Chen X. Dose-dependent immunomodulatory effects of metformin on human neonatal monocyte-derived macrophages. Cell Immunol. 2022 Jul;377:104557. doi: 10.1016/j.cellimm.2022.104557. Epub 2022 Jun 3. PMID 35679651

Идентификаторы

NCT: NCT07120971 · PRO55881

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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