2022-502492-32-00招募中2 期
A Global, Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of mRNA-3705 in Participants with Isolated Methylmalonic Acidemia Due to Methylmalonyl-CoA Mutase Deficiency
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- Moderna Inc.
- 入组人数
- 30
- 试验地点
- 10
- 主要终点
- Part I: Incidence and severity of TEAEs, including study drug–related and not related TEAEs, AESIs, SAEs, and TEAEs leading to treatment discontinuation.
研究概览
简要总结
Part I: Evaluate the safety and tolerability of mRNA-3705 administered via intravenous infusion to participants with isolated MMA due to MUT deficiency. Part II: Evaluate the efficacy of mRNA-3705 as assessed by the change in plasma methylmalonic acid levels Part III: Evaluate the safety and tolerability of mRNA-3705 administered via intravenous infusion to participants with isolated MMA due to MUT deficiency, and not eligible to participate in Part 2
研究设计
- 分配方式
- Randomized
- 主要目的
- Treatment
- 盲法
- Double (Investigator, Subject, Monitor)
入排标准
- 年龄范围
- 0 years 至 64 years（0-17 Years, 18-64 Years）
- 接受健康志愿者
- 是
入选标准
- •(Part 1 only) Participant is ≥1 year of age at the time of informed consent/assent.
- •(Part 1 only) Participant has a body weight of ≥11.0 kg at the Screening Visit.
- •Participant has a diagnosis of isolated MMA due to MUT deficiency confirmed by molecular genetic testing (see guidance in Section 8.1.2 for participants <23.3 kg).
- •Participant has a blood Vitamin B12 level equal to or above the lower limit of normal (based on laboratory reference range) confirmed in the Screening Period.
- •Participant or their legally authorized representative is willing and able to provide informed consent and/or assent as mandated by local regulations and is willing and able to comply with study-related assessments.
- •Sexually active participants of childbearing or reproductive potential agree to use a highly effective method of contraception, consistent with local regulations, during the study and for 3 months after the last administration of study drug.
- •(Part 1 only) Participants with parameters that indicate MMA clinical severity as described in Section 10.2.
- •(Part 2 only) Participants with 2 screening methylmalonic acid levels ≥400 μM, as described in Section 8.1.
- •(Parts 2& 3 only) Participant is ≥5 years of age at the time of informed consent/assent.
排除标准
- •Participant has a diagnosis of isolated MMA cb1A, cb1B, or cb1D enzymatic subtypes or methylmalonyl-CoA epimerase deficiency or combined MMA with homocystinuria.
- •Participant has any individual laboratory abnormalities achieving exclusionary thresholds defined in Table
- •Participant has previously received gene therapy for the treatment of MMA.
- •Participant has an eGFR <30 mL/min/1.73 m2, as estimated by the Schwartz formula for participants <18 years of age (Schwartz et al 2009), or by the Chronic Kidney Disease Epidemiology Collaboration creatinine-based formula for participants ≥18 years of age (Inker et al 2021), or receives long-term dialysis.
- •Participant has a corrected QT interval >480 ms using Bazett’s correction.
- •For participants of reproductive potential, the participant has a positive pregnancy test at the Screening Visit.
- •Participant is pregnant or breastfeeding.
- •Participant has a history of organ transplantation or planned organ transplantation during the period of study participation.
- •Participant has a history of hypersensitivity to any components of the study drug.
- •Participant has a history of hypersensitivity or contraindication to acetaminophen/paracetamol and/or ibuprofen or H1/H2 receptor blockers.
- •Participation in another clinical study of another investigational agent within 30 days before study entry or within 5 elimination half-lives of the investigational agent, whichever is longer.
- •Participant has undergone a major surgical procedure within 30 days before the Screening Visit (excludes central line, port, or feeding tube placement).
- •Participant has new uses or adjusted dosage of antibiotic therapy used to reduce propionate production within 2 weeks before first dose of study drug.
- •Any participant with a new or adjusted dosage of antibiotics may enter the Treatment Period after 2 weeks of stable antibiotic regimen.
- •This criterion has been removed and integrated into Exclusion Criterion 13 in Protocol Amendment
- •Participant has an active, unstable, or clinically significant medical condition not related to MMA or history of noncompliance that, in the Investigator’s opinion, could potentiate the risk while participating in this study, interfere with the interpretation of study results, or limit the participant’s participation in the study. This may include, but is not limited to, history of relevant food or drug allergies; history of cardiovascular, central nervous, gastrointestinal, or infectious disease; history of clinically significant pathology; and/or history of cancer.
- •Participant has received COVID-19 vaccination (generally 2 doses or a booster) within 28 days prior to first study drug administration. 17.This criterion has been removed in Protocol Amendment
- •Participant has a history of anaphylaxis/anaphylactoid reaction or severe hypersensitivity with infusions.
- •This criterion has been removed in Protocol Amendment
- •(Part 2 only) Participant has the mut- disease phenotype, as assessed by genotyping, clinical phenotype/presentation, or Vitamin B12-responsive MMA.
结局指标
主要结局
Part I: Incidence and severity of TEAEs, including study drug–related and not related TEAEs, AESIs, SAEs, and TEAEs leading to treatment discontinuation.
Part I: Incidence and severity of TEAEs, including study drug–related and not related TEAEs, AESIs, SAEs, and TEAEs leading to treatment discontinuation.
Part II: Percentage change in plasma methylmalonic acid levels at 3 months of treatment in participants treated with mRNA-3705 compared to placebo.
Part II: Percentage change in plasma methylmalonic acid levels at 3 months of treatment in participants treated with mRNA-3705 compared to placebo.
Part III: Incidence and severity of TEAEs, including study drug-related and not related TEAEs, AESIs, SAEs, and TEAEs leading to treatment discontinuation.
Part III: Incidence and severity of TEAEs, including study drug-related and not related TEAEs, AESIs, SAEs, and TEAEs leading to treatment discontinuation.
次要结局
- Part I: - Percentage change in plasma methylmalonic acid levels from baseline (pretreatment) to postdose levels measured after single and repeated administrations of mRNA-3705. - Estimation of PD parameters after single and repeated administrations of mRNA-3705, including AUC_Below_B, AUC_Net_B, and Emax - Percentage change in plasma 2-MC levels from baseline (pretreatment) to levels measured after single and repeated administrations of mRNA-3705.
- Part I (continuation): - Estimation of hMUT mRNA PK parameters including, but not limited to, Cmax, Tmax, AUC, t½, CL, Vz and Vss. - Presence and titers of anti-PEG antibodies.
- Part II: - Estimation of PK parameters of hMUT (anti-hMUT) mRNAs including, but not limited to, Cmax, Tmax, AUC, t½, CL, and Vz. - Measurement of SM-86 after single and repeated dosing.
- Part II(continuation): - Percentage change in plasma 2-MC at 3 months of treatment in participants treated with mRNA-3705 compared to placebo. - Change from baseline in PedsQL™ Physical Function score at 3 months of treatment in participants treated with mRNA-3705 compared to placebo. - Annualized frequency of MMA -related hospitalizations up until 3 months of treatment. - Annualized frequency of MDEs up until 3 months of treatment, both overall and by severity.
- Part II(continuation): - Change in: − PedsQL™ Total Score from baseline(pretreatment) − IGA-S and CrGI-S from baseline(pretreatment) − IGA-I and CrGI-I from the Dose 2 visit - Incidence and severity of TEAEs. - Incidence and severity of SAEs. - Incidence and severity of AESIs (eg, IRR and hypersensitivity). - Incidence and severity of TEAEs leading to treatment discontinuation. - Presence and titers of antibodies against PEG (anti-PEG) and hMUT (anti-hMUT).
- Part III: - Percentage change in plasma methylmalonicacid levels at 3 months of treatment - Percentage change in plasma 2-MC levels at 3months of treatment - Estimation of hMUT mRNA PK parametersincluding, but not limited to, Cmax, Tmax, AUC, t½, CL, and Vz - Change from Baseline in PedsQL™ PhysicalFunction score at 3 months of treatment - Annualized frequency of MMA-relatedhospitalizations up until 3 months of treatment
- Part III: - Annualized frequency of MDEs up until 3months of treatment, both overall and by severity - Change in: − PedsQL™ Total Score from baseline(pretreatment). − IGA-S and CrGI-S from baseline(pretreatment). − IGA-I and CrGI-I from the Dose 2 visit - Presence and titers of antibodies against PEG(anti-PEG) and hMUT (anti-hMUT)
研究者
Moderna WeCare Team
Scientific
Moderna Therapeutics Inc.
研究点 (10)
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