---
title: "Phase 1b Multiple Ascending Dose Trial (NCT04143802)"
description: "A Phase 1b, randomized, double-blind, placebo-controlled, multiple-ascending dose trial evaluating safety, tolerability, pharmacokinetics, and pharmacodynamics of retatrutide in adults with type 2 diabetes."
url: https://retatrutide.med/clinical-trials/phase-1-multiple-ascending-dose
date: 2024-08-15
lastUpdated: 2026-03-15
phase: "1"
trialName: "Phase 1b MAD Trial"
status: "results-published"
nctId: "NCT04143802"
source: retatrutide.med
sourceType: "clinical trial"
license: CC-BY-NC-SA-4.0
canonical: https://retatrutide.med/clinical-trials/phase-1-multiple-ascending-dose
---
## Study Overview

The Phase 1b multiple ascending dose (MAD) trial of retatrutide was a critical early clinical study that provided the first evidence of dose-dependent efficacy in humans with type 2 diabetes. Published by Urva et al. in The Lancet in November 2022, this trial established the pharmacokinetic profile that would support once-weekly dosing and generated the safety data needed to advance into Phase 2.

## Study Design

### Design

Randomized, double-blind, placebo-controlled, multiple-ascending dose trial conducted at multiple U.S. centers.

### Duration

12 weeks of treatment with follow-up.

### Population

72 adults aged 18-70 years with type 2 diabetes (HbA1c 7.0-10.5%) treated with diet/exercise alone or with stable metformin. BMI 23-50 kg/m².

### Dose Cohorts

Participants were randomized across ascending dose cohorts:
- 0.5 mg weekly
- 1.5 mg weekly
- 3.0 mg weekly (with and without escalation)
- 4.5 mg weekly (with escalation)
- 6.0 mg weekly (with escalation)
- 9.0 mg weekly (with escalation)
- 12.0 mg weekly (with escalation)

Within each cohort, participants were randomized 3:1 to retatrutide or placebo.

## Pharmacokinetic Results

The trial established key PK parameters:
- **Half-life**: Approximately 6 days, confirming suitability for once-weekly injection
- **Tmax**: 12-72 hours post-injection
- **Steady state**: Achieved by approximately week 4-5 of weekly dosing
- **Dose proportionality**: Exposure increased in an approximately dose-proportional manner

## Efficacy Signals

Despite the short 12-week treatment duration, robust dose-dependent efficacy was observed:

| Dose | HbA1c Change | Weight Change |
|------|-------------|---------------|
| Placebo | -0.01% | -0.4 kg |
| 0.5 mg | -0.43% | -3.19 kg |
| 3.0 mg (escalation) | -1.19% | -7.18 kg |
| 6.0 mg (escalation) | -1.38% | -7.84 kg |
| 9.0 mg (escalation) | -1.52% | -8.65 kg |
| 12.0 mg (escalation) | -1.56% | -8.96 kg |

## Safety

The adverse event profile was consistent with the GLP-1 receptor agonist class:
- **Most common**: Nausea (26%), diarrhea (21%), vomiting (13%)
- **Dose escalation benefit**: GI adverse events were less frequent and less severe with gradual dose escalation compared to fixed dosing
- **No pancreatitis, medullary thyroid carcinoma, or major hypoglycemia**
- **Heart rate**: Small dose-dependent increases observed (2-4 bpm)

## Significance

This trial was pivotal in establishing:
1. **Once-weekly feasibility**: The ~6-day half-life validated weekly dosing
2. **Dose escalation strategy**: Gradual titration improved tolerability, informing Phase 2 design
3. **Triple agonist proof-of-concept**: Demonstrated that simultaneous activation of GIP, GLP-1, and glucagon receptors produced metabolic benefits without unexpected safety concerns
4. **Unprecedented early weight loss**: The magnitude of weight reduction at only 12 weeks exceeded what most single-agonist therapies achieve at this timepoint

## Publication

Urva S, Coskun T, Loh MT, et al. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. *The Lancet*. 2022;400:1869-1881.