Which trial states that triple therapy is better than double therapy as a first-line treatment for Cystic Fibrosis (CF)?

Triple Therapy in Cystic Fibrosis: First-Line Evidence

The trials demonstrating triple therapy superiority over double therapy as first-line treatment in cystic fibrosis are VX17-445-102 (published in NEJM 2019) and the phase 3b trial NCT04105972 (published in Lancet Respiratory Medicine 2022), both evaluating elexacaftor-tezacaftor-ivacaftor versus placebo or tezacaftor-ivacaftor alone. 1, 2

Key Clinical Trials Establishing Triple Therapy Superiority

VX17-445-102 Trial (NEJM 2019)

This phase 3 randomized, double-blind, placebo-controlled trial enrolled 403 patients aged ≥12 years with cystic fibrosis who were heterozygous for F508del-CFTR and a minimal-function mutation (F508del-MF genotype). 2

Primary outcomes at 4 weeks demonstrated:

• Absolute increase in percent predicted FEV1 of 13.8 percentage points compared to placebo (P<0.001), sustained at 14.3 points through 24 weeks 2
• 63% reduction in pulmonary exacerbation rate compared to placebo (P<0.001) 2
• 20.2-point improvement in CFQ-R respiratory domain score (exceeding the 4-point minimum clinically important difference by fivefold) (P<0.001) 2
• 41.8 mmol/L reduction in sweat chloride concentration (P<0.001), indicating improved CFTR function 2

NCT04105972 Trial (Lancet Respiratory Medicine 2022)

This phase 3b trial specifically compared elexacaftor-tezacaftor-ivacaftor (triple therapy) directly against tezacaftor-ivacaftor (double therapy) in 175 patients homozygous for F508del-CFTR mutation, aged ≥12 years. 1

Direct head-to-head comparison over 24 weeks showed:

• CFQ-R respiratory domain score increased by 17.1 points with triple therapy versus only 1.2 points with double therapy (treatment difference 15.9 points, P<0.0001) 1
• Percent predicted FEV1 increased by 11.2 percentage points with triple therapy versus 1.0 percentage point with double therapy (treatment difference 10.2 percentage points, P<0.0001) 1
• Sweat chloride decreased by 46.2 mmol/L with triple therapy versus 3.4 mmol/L with double therapy (treatment difference -42.8 mmol/L, P<0.0001) 1

Safety Profile Comparison

Triple therapy demonstrated superior tolerability compared to double therapy:

• Serious adverse events occurred in only 6% of triple therapy patients versus 16% in double therapy patients 1
• Most adverse events (80% in triple therapy group) were mild or moderate in severity 1
• Treatment discontinuation due to adverse events occurred in only 1% of triple therapy patients versus 2% in double therapy patients 1

Pediatric Evidence (Ages 6-11 Years)

A phase 3b randomized, placebo-controlled trial in 121 children aged 6-11 years with F508del-MF genotypes demonstrated that triple therapy produced: 3

• 2.26-unit decrease in lung clearance index (LCI2.5) compared to placebo (P<0.0001) 3
• 11.0 percentage point improvement in percent predicted FEV1 compared to placebo 3
• 51.2 mmol/L reduction in sweat chloride compared to placebo 3

Clinical Implications for First-Line Use

Triple therapy (elexacaftor-tezacaftor-ivacaftor) should be initiated as first-line treatment in all CF patients aged ≥6 years with at least one F508del-CFTR mutation, including those homozygous for F508del or heterozygous with a minimal-function mutation. 1, 2, 3

The magnitude of benefit is clinically transformative, with FEV1 improvements exceeding 10 percentage points—a threshold associated with substantial mortality reduction in CF populations. 1, 2

Dosing by weight for pediatric patients:

• Children <30 kg: elexacaftor 100 mg once daily, tezacaftor 50 mg once daily, ivacaftor 75 mg every 12 hours 3
• Children ≥30 kg and adults: elexacaftor 200 mg once daily, tezacaftor 100 mg once daily, ivacaftor 150 mg every 12 hours 3

Important Caveat

If skin rash develops (reported adverse effect), a gradual desensitization protocol can be implemented rather than permanent discontinuation, given the dramatic clinical benefits and risk of rapid lung function decline upon cessation. 4