Clinical Trial for Age 1 to <2 Years


Safety Evaluated in Patients Aged 1 to 2 Years Who Are Homozygous for the F508del-CFTR Mutation




Trial 7 | Open-Label Safety Study (Part B)1,2


Trial 7 was a 24-week, open-label study assessing the safety of ORKAMBI in 46 patients aged 1 through 2 years with CF who were homozygous for the F508del-CFTR mutation. Patients received ORKAMBI granules (if 7 to <9 kg: lumacaftor 75 mg/ivacaftor 94 mg; if 9 to <14 kg: lumacaftor 100 mg/ivacaftor 125 mg; if ≥14 kg: lumacaftor 150 mg/ivacaftor 188 mg) mixed with 1 teaspoon (5 mL) of soft food or liquid and administered orally every 12 hours with fat-containing food. All patients continued to take their prescribed CF therapies (including during the 2-week washout period). The primary endpoint was safety and tolerability up to Week 24.


Trial 7 | Limitations and Disclosures2

  • The study was open-label and not placebo controlled; therefore, causality cannot be attributed
  • All patients in the study were on active drug, which may have introduced bias related to awareness of treatment

Impact of COVID-192

  • Trial 7 was conducted during the COVID-19 pandemic. Vertex implemented safety measures, including at-home safety visits, to provide patients the opportunity to continue the study and minimize risk of COVID-19 exposure through travel

Back to top



The Primary Endpoint Was Safety and Tolerability up to Week 24.

The Safety Profile of ORKAMBI in Patients Aged 1 through 2 Years Was Similar to Patients Aged 2 Years and Older1,2


Liver-Related Adverse Events

Elevated ALT or ASTORKAMBI Total, N=46 (%)
>3 x ULN5 (10.9)
>5 x ULN2 (4.3)
>8 x ULN1 (2.2)
  • No patients had total bilirubin levels >2 x ULN
  • No patients experienced treatment interruptions due to transaminase elevations

Discontinuations and Serious AEs


  • One patient (2.2%) discontinued treatment with ORKAMBI due to an AE (transaminase elevations)
  • Five patients (10.9%) experienced serious AEs (three with infective pulmonary exacerbations of CF, one with post-procedural fever, and one with DIOS), all of which were considered by study investigators to be mild or moderate in severity


  • One patient (2.2%) experienced a respiratory-related AE (dyspnea)
    • It occurred on Day 1 of Trial 7, resulting in treatment interruption. ORKAMBI use resumed as normal on Day 2, and the event did not recur

Back to top



Trial 7: Sweat Chloride Results (Pharmacodynamics)

In patients treated with ORKAMBI, sweat chloride reductions were observed as early as Week 41,2

Secondary endpoint: mean absolute change from baseline in sweat chloride concentration Secondary endpoint: mean absolute change from baseline in sweat chloride concentration

Mean Absolute Change From Baseline in Sweat Chloride

  • From baseline at Week 24 (n=24): -29.1 mmol/L (95% CI: -34.8, -23.4) reduction 
  • After washout, from Week 24 to Week 26 (n=25), increased to +27.3 mmol/L (95% Cl: 22.3, 32.3)

There was no direct correlation between decrease in sweat chloride level and improvement in lung function (ppFEV1)1

AE, adverse event; ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; Cl, confidence interval; DIOS, distal intestinal obstruction syndrome: ppFEV1, percent predicted forced expiratory volume in 1 second; ULN, upper limit of normal.

Important Safety Information

Warnings and Precautions

Use in Patients With Advanced Liver Disease

  • Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension while receiving ORKAMBI. Use ORKAMBI with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dose should be reduced

Indication and Usage

ORKAMBI is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients aged 1 year and older who are homozygous for the F508del mutation in the CFTR gene. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.

Limitations of Use
The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation.

Liver-related Events

  • Serious adverse reactions related to elevated transaminases have been reported in patients with CF receiving ORKAMBI. In some instances, these elevations have been associated with concomitant elevations in total serum bilirubin
  • It is recommended that ALT, AST, and bilirubin be assessed prior to initiating ORKAMBI, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered. Patients who develop increased ALT, AST, or bilirubin should be closely monitored until the abnormalities resolve
  • Dosing should be interrupted in patients with ALT or AST >5 x upper limit of normal (ULN) when not associated with elevated bilirubin. Dosing should also be interrupted in patients with ALT or AST elevations >3 x ULN when associated with bilirubin elevations >2 x ULN. Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing

Hypersensitivity Reactions, Including Anaphylaxis

  • Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the postmarketing setting. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue ORKAMBI and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with ORKAMBI

Respiratory Events

  • Respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal) were observed more commonly in patients during initiation of ORKAMBI compared to those who received placebo. These events have led to drug discontinuation and can be serious, particularly in patients with advanced lung disease (percent predicted FEV1 (ppFEV1) <40). Clinical experience in patients with ppFEV1 <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy

Effect on Blood Pressure

  • Increased blood pressure has been observed in some patients treated with ORKAMBI. Blood pressure should be monitored periodically in all patients being treated with ORKAMBI

Drug Interactions

  • Substrates of CYP3A
    Lumacaftor is a strong inducer of CYP3A. Administration of ORKAMBI may decrease systemic exposure of medicinal products that are substrates of CYP3A, which may decrease therapeutic effect. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended. ORKAMBI may substantially decrease hormonal contraceptive exposure, reducing their effectiveness and increasing the incidence of menstruation-associated adverse reactions, e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI
  • Strong CYP3A Inducers
    Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes. Use of ORKAMBI with strong CYP3A inducers, such as rifampin, significantly reduces ivacaftor exposure, which may reduce the therapeutic effectiveness of ORKAMBI. Therefore, co-administration with strong CYP3A inducers is not recommended


  • Cases of non-congenital lens opacities have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with ORKAMBI


Serious Adverse Reactions

  • Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with ORKAMBI included pneumonia, hemoptysis, cough, increased blood creatine phosphokinase, and transaminase elevations. These occurred in 1% or less of patients

Most Common Adverse Reactions

  • The most common adverse reactions in patients age 12 years and older in Phase 3 trials (Trials 1 and 2) occurring in ≥5% of patients treated with ORKAMBI (N=369) vs placebo (N=370) and at a rate higher than placebo were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, and influenza
  • The safety profile in patients age 6 through 11 years from an open-label trial (Trial 3; N=58) and a placebo-controlled trial (Trial 4; patients treated with ORKAMBI, N=103 vs placebo, N=101) was similar to that observed in Trials 1 and 2. Additional common adverse reactions were reported in Trial 4, but were not reported in Trials 1 and 2. The adverse reactions in Trial 4 that occurred in ≥5% of patients treated with ORKAMBI with an incidence of ≥3% higher than placebo included: productive cough, nasal congestion, headache, abdominal pain upper, and sputum increased
  • The safety profile in patients age 2 through 5 years from an open-label trial (Trial 6; N=60) was similar to that in patients aged 6 years and older. The safety profile in patients age 1 through 2 years from an open-label trial (Trial 7; N=46) was similar to that in patients aged 2 years and older


Pediatric Use

  • The safety and effectiveness of ORKAMBI in patients with CF younger than 1 year of age have not been established

Click here to access full Prescribing Information for ORKAMBI.


1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; August 2023. 2. Rayment JH, Asfour F, Rosenfeld M, et al; VX16-809-122 Study Group. A phase 3, open-label study of lumacaftor/ivacaftor in children 1 to less than 2 years of age with cystic fibrosis homozygous for F508del-CFTR. Am J Respir Crit Care Med. Published online June 30, 2022. doi:10.1164/rccm.202204-0734OC