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NCT Number: NCT07826988

Adaptive Platform Trial for Pain Management in Sickle Cell Vaso-Occlusive Crisis

Sickle cell disease (SCD) is a severe hemoglobinopathy, characterized by recurrent vaso-occlusive crises (VOC) causing intense pain and frequent hospitalizations in adult patients. Current French and British guidelines recommend rapid administration of strong opioids, primarily through patient-controlled analgesia (PCA), as the reference treatment for hospitalized patients experiencing VOC. However, opioid use is associated with dose-dependent adverse effects, including nausea, constipation, pruritus, sedation, and hypoventilation, the latter representing a risk factor for acute chest syndrome.

The hypothesis underlying this study is that multimodal analgesia-combining morphine PCA with co-analgesics such as paracetamol-can significantly reduce morphine consumption during hospitalization compared to opioid-only analgesia, while maintaining effective pain control. Although several co-analgesic agents (paracetamol, NSAIDs, nefopam, tramadol, ketamine) are recommended by expert guidelines, including those from the American Society of Hematology (2020) and French recommendations (2025), the level of evidence supporting their use in adult sickle cell patients remains low or non-existent for most agents, with no randomized controlled trials available for nefopam, tramadol, or ketamine.

Using an adaptive platform design, this trial aims to compare multiple analgesic strategies against standard opioid-based care, generating higher-quality evidence to optimize pain management protocols for adult patients experiencing VOC

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Key information

Conditions

Sickle Cell Disease Agnosia Anemia Anemia, Hemolytic Anemia, Hemolytic, Congenital Anemia, Sickle Cell Congenital, Hereditary, and Neonatal Diseases and Abnormalities Genetic Diseases, Inborn Hematologic Diseases Hemic and Lymphatic Diseases Hemoglobinopathies Nervous System Diseases Neurobehavioral Manifestations Neurologic Manifestations Pathological Conditions, Signs and Symptoms Perceptual Disorders Signs and Symptoms Vaso-Occlusive Crises Vaso-occlusive Crisis

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Adult patients (age ≥18 years)
  • Diagnosed with major sickle cell syndrome (SS homozygous, SC or Sβ° or Sβ+ thalassemia compound heterozygous)
  • Hospitalized and presenting with a vaso-occlusive crisis (VOC), defined as acute pain or tenderness affecting at least one part of the body, including the limbs, ribs, sternum, head (skull), spine, and/or pelvis, not attributable to other causes
  • Requiring intravenous morphine or its derivatives
  • Informed consent obtained from the patient (or from a trusted support person, family member, or relative), or emergency inclusion procedure in cases where the patient is unable to consent and no trusted support person, family member, or relative is available

Exclusion criteria

  • Refusal to participate
  • Pregnant or breastfeeding patient
  • Administration of one of the interventional group treatments within 4 hours prior to inclusion
  • Intravenous morphine treatment for more than 24 hours
  • Patient already included in the study within the previous 3 months
  • Patient receiving long-term opioid therapy
  • Not affiliated with a social security scheme, or patient under State Medical Aid (AME)
  • Patient under legal protection measures (guardianship / family authorization with representation mandate / future protection mandate) or under supervised guardianship (curatelle)
  • Patient deprived of liberty
  • Participation in another clinical trial involving a drug
  • Participation in the PAMAVOC trial within the previous 3 months
  • Contraindication to standard VOC treatment:
  • Hypersensitivity to opioids
  • Opioid-induced hyperalgesia, defined by increased pain on nociceptive testing, topographic extension, or the onset of allodynia with increasing opioid doses
  • Renal impairment, defined as creatinine clearance ≤30 mL/minute
  • Hepatocellular impairment, defined as prothrombin time <40%
  • Impaired consciousness, defined as a Glasgow Coma Scale score ≤13/15

Exclusion from a Specific Intervention (randomization possible to other study arms):

  • Hypersensitivity to the active substance or to any of the excipients
  • Respective contraindications to nefopam, tramadol, ketoprofen, and ketamine, as described in their respective Summaries of Product Characteristics (SmPC)

Treatment and study plan

Group 02 Paracetamol + Morphine + Ketamine

Drug

Participants receive intravenous paracetamol and morphine via PCA. In case of hyperalgic VOC, low-dose ketamine may be added as a co-analgesic, off-label, according to the treating physician's judgment.

Group 01 Control: Paracetamol + Morphine

Drug

Participants receive intravenous paracetamol and morphine via patient-controlled analgesia (PCA). In case of hyperalgic VOC, morphine dosage may be increased according to the treating physician's judgment

Group 03 : Paracetamol + Morphine + Nefopam

Drug

Participants receive intravenous paracetamol, morphine via PCA, and nefopam. In case of hyperalgic VOC, morphine dosage may be increased according to the treating physician's judgment.

Group 04 : Paracetamol + Morphine + Nefopam + Ketamine

Drug

Participants receive intravenous paracetamol, morphine via PCA, and nefopam. In case of hyperalgic VOC, low-dose ketamine may be added as a co-analgesic, off-label, according to the treating physician's judgment.

Goup 05 : Paracetamol + Morphine + Tramadol

Drug

Participants receive intravenous paracetamol, morphine via PCA, and tramadol. In case of hyperalgic VOC, morphine dosage may be increased according to the treating physician's judgment.

Group 6 : Paracetamol + Morphine + Tramadol + Ketamine

Drug

Participants receive intravenous paracetamol, morphine via PCA, and tramadol. In case of hyperalgic VOC, low-dose ketamine may be added as a co-analgesic, off-label, according to the treating physician's judgment.

Group 7 : Paracetamol + Morphine + Ketoprofen

Drug

Participants receive intravenous paracetamol, morphine via PCA, and ketoprofen. In case of hyperalgic VOC, morphine dosage may be increased according to the treating physician's judgment.

Group 08 : Paracetamol + Morphine + Ketoprofen + Ketamine

Drug

Participants receive intravenous paracetamol, morphine via PCA, and ketoprofen. In case of hyperalgic VOC, low-dose ketamine may be added as a co-analgesic, off-label, according to the treating physician's judgment.

Primary outcomes

  1. Time to resolution of vaso-occlusive crisis (VOC)

    Time frame: Up to 14 days after randomization.

    Time to resolution of vaso-occlusive crisis is defined as the time from randomization to discontinuation of intravenous opioid therapy, measured in hours.

Secondary outcomes

  1. Intravenous Morphine Consumption

    Time frame: From admission to discharge, assessed up to 14 dayss)

    Cumulative dose (mg) and mean daily dose (mg/day) of intravenous morphine.

  2. Transfusion Requirements

    Time frame: From admission to discharge, assessed up to 14 days

    Number of red blood cell units transfused.

  3. Intensive Care Unit Admission

    Time frame: From admission to discharge, assessed up to 14 days

    Admission to intensive care unit during hospitalization.

  4. Morphine-Related Adverse Effects

    Time frame: Within 3 months (+/- 15 days)

    Constipation, sedation (impaired consciousness requiring opioid discontinuation or naloxone administration), vomiting, and secondary acute chest syndrome (new pulmonary infiltrate associated with a clinical sign such as fever, or a respiratory sign such as chest pain or dyspnea).

  5. Length of Hospital Stay

    Time frame: From admission to discharge, assessed up to 14 days

    Duration of hospitalization, measured in days

  6. Hyperalgic Vaso-Occlusive Crisis

    Time frame: from randomization to discontinuation of intravenous opioid therapy Up to 14 days

    Uncontrolled pain requiring morphine titration >1 mg/kg or total intravenous morphine consumption >2 mg/kg/24h.

  7. Refractory Vaso-Occlusive Crisis

    Time frame: From randomization to discontinuation of intravenous opioid therapy Up to 14 days

    Visual analog scale (VAS) score >7/10 after administration of study treatments and a new morphine titration (1 mg/kg).

  8. Adverse Effects of Investigational Medicinal Products

    Time frame: Within 3 months (+/- 15 days)

    Including nefopam (seizure); NSAIDs (acute kidney injury, KDIGO stage >0; gastrointestinal or other bleeding); tramadol (seizure, liver function abnormalities, impaired consciousness with GCS <14/15); ketamine (liver function abnormalities, hallucinations, impaired consciousness with GCS <14/15, venous access complications).

  9. In-Hospital Mortality

    Time frame: Duration of hospital stay, assessed up to 14 days

    Death occurring during hospitalization.

  10. Unplanned Readmission

    Time frame: Within 3 months (+/- 15 days) after discharge

    Unplanned hospital readmission within 3 months following the index hospitalization.

Study contacts

Contact information is provided by the study sponsor or research team.

Samia BALOUL

CONTACT

[email protected]

01 49 81 33 85

Ségolène GENDREAU

CONTACT

[email protected]

01.45.17.85.06

Sponsors and collaborators

Lead sponsor

Assistance Publique - Hôpitaux de Paris

Other

Registry information

Official study title

Adaptive Platform Trial for Pain Management During Vaso-Occlusive Crisis in Adult Patients With Sickle Cell Disease

Acronym: PAMAVOC

Important dates

Study start
2026
Primary completion
2029
Study completion
2030
First posted
Sep 18, 2026
Registry last updated
Sep 18, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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