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PP100-01 (Calmangafodipir) for Overdose of Paracetamol (POP)

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ClinicalTrials.gov Identifier: NCT03177395
Recruitment Status : Enrolling by invitation
First Posted : June 6, 2017
Last Update Posted : June 5, 2018
Sponsor:
Collaborators:
University of Edinburgh
NHS Lothian
Information provided by (Responsible Party):
PledPharma AB

Brief Summary:
Investigate the safety and tolerability of PP100-01 add-on treatment to the 12hr NAC treatment regime in patients treated for paracetamol/acetaminophen overdose (POD) when NAC treatment is initiated before 24hours post POD.

Condition or disease Intervention/treatment Phase
Paracetamol Overdose Drug: PP100-01 (calmangafodipir) Phase 1

Detailed Description:

The study will be an open label, randomised, exploratory, rising dose design, NAC controlled, phase 1 safety and tolerability study in patients treated with NAC for paracetamol/acetaminophen overdose.

Entry into the study will depend on the patient's blood results confirming the need for NAC. A total of 24 patients will be assigned into one of 3 dosing cohorts of 8 patients (N=6 for PP100-01 and NAC; N=2 for NAC alone).

The study will primarily evaluate safety and tolerability for treatment with PP100-01 in combination with NAC as compared to NAC alone.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomised Open Label Exploratory, Safety and Tolerability Study With PP100-01 in Patients Treated With the 12-hour Regimen of N-Acetylcysteine for Paracetamol/Acetaminophen Overdose (The POP Trial)
Actual Study Start Date : June 8, 2017
Estimated Primary Completion Date : August 8, 2018
Estimated Study Completion Date : December 31, 2018

Arm Intervention/treatment
No Intervention: Acetylcysteine (N-acetylcysteine; NAC)
NAC infusion 100mg/kg in 200ml 'loading dose' at timepoint '0'. 12 hour NAC regime will be continued with the second dose: 200mg/kg NAC in 1000ml i.v. over 10hr as per standard care protocol in NHS Lothian.
Experimental: PP100-01 (Calmangafodipir)+ NAC

In addition to the standard care NAC regime, participants will be allocated into a dosing cohort to receive:

  • Group A: PP100-01 (2 umol/kg calmangafodipir) after the "loading" dose of NAC
  • Group B: PP100-01 (5 umol/kg calmangafodipir) after the "loading" dose of NAC
  • Group C: PP100-01 (10 umol/kg calmangafodipir) after the "loading" dose of NAC

PP100-01 treatment is administered intravenously over 5 minutes.

Drug: PP100-01 (calmangafodipir)
PP100-01
Other Name: PP100-01




Primary Outcome Measures :
  1. Safety Events [ Time Frame: 90 days ]
    Adverse Events and Serious Adverse Events


Secondary Outcome Measures :
  1. Clinical Observations- Pulse Rate [ Time Frame: Baseline ]
    Pulse rate (bpm)

  2. Clinical Observations- Pulse rate [ Time Frame: 2 hours ]
    Pulse rate (bpm)

  3. Clinical Observations- pulse rate [ Time Frame: 2.5 hours ]
    Pulse rate (bpm)

  4. Clinical Observations- pulse rate [ Time Frame: 10 hours ]
    Pulse rate (bpm)

  5. Clinical Observations- pulse rate [ Time Frame: 20 hours ]
    Pulse rate (bpm)

  6. Clinical Observations- BP [ Time Frame: Baseline ]
    Blood pressure (mm Hg)

  7. Clinical Observations- BP [ Time Frame: 2 hours ]
    Blood pressure (mm Hg)

  8. Clinical Observations- BP [ Time Frame: 2.5 hours ]
    Blood pressure (mm Hg)

  9. Clinical Observations- BP [ Time Frame: 10 hours ]
    Blood pressure (mm Hg)

  10. Clinical Observations- BP [ Time Frame: 20 hours ]
    Blood pressure (mm Hg)

  11. Clinical Observations- Respiratory rate [ Time Frame: Baseline ]
    Respiratory rate (rpm)

  12. Clinical Observations-Respiratory rate [ Time Frame: 2 hours ]
    Respiratory rate (rpm)

  13. Clinical Observations- Respiratory rate [ Time Frame: 2.5 hours ]
    Respiratory rate(rpm)

  14. Clinical Observations- Respiratory rate [ Time Frame: 10 hours ]
    Respiratory rate (rpm)

  15. Clinical Observations- Respiratory rate [ Time Frame: 20 hours ]
    Respiratory rate (rpm)

  16. Clinical Observations- Pulse Oximetry [ Time Frame: Baseline ]
    Pulse oximetry (%)

  17. Clinical Observations- Pulse Oximetry [ Time Frame: 2 hours ]
    Pulse oximetry (%)

  18. Clinical Observations- Pulse Oximetry [ Time Frame: 2.5 hours ]
    Pulse oximetry (%)

  19. Clinical Observations- Pulse Oximetry [ Time Frame: 10 hours ]
    Pulse oximetry (%)

  20. Clinical Observations- Pulse Oximetry [ Time Frame: 20 hours ]
    Pulse oximetry (%)

  21. Clinical Observations- Temperature [ Time Frame: Baseline ]
    Temperature (Degrees Celsius)

  22. Clinical Observations- Temperature [ Time Frame: 2 hours ]
    Temperature (Degrees Celsius)

  23. Clinical Observations- Temperature [ Time Frame: 2.5 hours ]
    Temperature (Degrees Celsius)

  24. Clinical Observations- Temperature [ Time Frame: 10 hours ]
    Temperature (Degrees Celsius)

  25. Clinical Observations- Temperature [ Time Frame: 20 hours ]
    Temperature (Degrees Celsius)

  26. Haematology and clinical biochemistry parameters- APAP [ Time Frame: screening ]
    APAP concentration

  27. Haematology and clinical biochemistry parameters-APAP [ Time Frame: 10 hours ]
    APAP concentration

  28. Haematology and clinical biochemistry parameters-APAP [ Time Frame: 20 hours ]
    APAP concentration

  29. Haematology and clinical biochemistry parameters- INR [ Time Frame: screening ]
    INR (no units)

  30. Haematology and clinical biochemistry parameters- INR [ Time Frame: 2hours ]
    INR (no units)

  31. Haematology and clinical biochemistry parameters- INR [ Time Frame: 10hours ]
    INR (no units)

  32. Haematology and clinical biochemistry parameters- INR [ Time Frame: 20hours ]
    INR (no units)

  33. Haematology and clinical biochemistry parameters- ALT [ Time Frame: screening ]
    ALT (U/L)

  34. Haematology and clinical biochemistry parameters- ALT [ Time Frame: 2 hours ]
    ALT (U/L)

  35. Haematology and clinical biochemistry parameters-ALT [ Time Frame: 10 hours ]
    ALT (U/L)

  36. Haematology and clinical biochemistry parameters-ALT [ Time Frame: 20 hours ]
    ALT (U/L)

  37. Haematology and clinical biochemistry parameters-ALP [ Time Frame: Screening ]
    ALP (U/L)

  38. Haematology and clinical biochemistry parameters-ALP [ Time Frame: 2 hours ]
    ALP (U/L)

  39. Haematology and clinical biochemistry parameters-ALP [ Time Frame: 10 hours ]
    ALP (U/L)

  40. Haematology and clinical biochemistry parameters-ALP [ Time Frame: 20 hours ]
    ALP (U/L)

  41. Haematology and clinical biochemistry parameters-Bilirubin [ Time Frame: Screening ]
    Bilirubin (umol/L)

  42. Haematology and clinical biochemistry parameters-Bilirubin [ Time Frame: 2 hours ]
    Bilirubin (umol/L)

  43. Haematology and clinical biochemistry parameters-Bilirubin [ Time Frame: 10 hours ]
    Bilirubin (umol/L)

  44. Haematology and clinical biochemistry parameters-Bilirubin [ Time Frame: 20 hours ]
    Bilirubin (umol/L)

  45. Haematology and clinical biochemistry parameters-Creatinine [ Time Frame: Screening ]
    Creatinine (umol/L)

  46. Haematology and clinical biochemistry parameters-Creatinine [ Time Frame: 2 hours ]
    Creatinine (umol/L)

  47. Haematology and clinical biochemistry parameters-Creatinine [ Time Frame: 10 hours ]
    Creatinine (umol/L)

  48. Haematology and clinical biochemistry parameters-Creatinine [ Time Frame: 20hours ]
    Creatinine (umol/L)

  49. Haematology and clinical biochemistry parameters-HB [ Time Frame: Screening ]
    Haemoglobin (g/L)

  50. Haematology and clinical biochemistry parameters-HB [ Time Frame: 10 hours ]
    Haemoglobin (g/L)

  51. Haematology and clinical biochemistry parameters-HB [ Time Frame: 20 hours ]
    Haemoglobin (g/L)

  52. Haematology and clinical biochemistry parameters-Urea [ Time Frame: Screening ]
    Urea (mmol/L)

  53. Haematology and clinical biochemistry parameters-Urea [ Time Frame: 10 hours ]
    Urea (mmol/L)

  54. Haematology and clinical biochemistry parameters-Urea [ Time Frame: 20 hours ]
    Urea (mmol/L)

  55. Haematology and clinical biochemistry parameters-Na [ Time Frame: Screening ]
    Sodium (mmol/L)

  56. Haematology and clinical biochemistry parameters-Na [ Time Frame: 10 hours ]
    Sodium (mmol/L)

  57. Haematology and clinical biochemistry parameters-Na [ Time Frame: 20 hours ]
    Sodium (mmol/L)

  58. Haematology and clinical biochemistry parameters- Potassium [ Time Frame: Screening ]
    Potassium (mmol/L)

  59. Haematology and clinical biochemistry parameters- Potassium [ Time Frame: 10 hours ]
    Potassium (mmol/L)

  60. Haematology and clinical biochemistry parameters- Potassium [ Time Frame: 20 hours ]
    Potassium (mmol/L)

  61. Haematology and clinical biochemistry parameters-MCV [ Time Frame: Screening ]
    MCV (fL)

  62. Haematology and clinical biochemistry parameters-MCV [ Time Frame: 10 hours ]
    MCV (fL)

  63. Haematology and clinical biochemistry parameters-MCV [ Time Frame: 20 hours ]
    MCV (fL)

  64. Haematology and clinical biochemistry parameters-WBC [ Time Frame: Screening ]
    WBC (x10*9/L)

  65. Haematology and clinical biochemistry parameters-WBC [ Time Frame: 10 hours ]
    WBC (x10*9/L)

  66. Haematology and clinical biochemistry parameters-WBC [ Time Frame: 20 hours ]
    WBC(x10*9/L)

  67. Experimental biomarkers in serum/plasma-MiR122 [ Time Frame: 2hours ]
    MiR122

  68. Experimental biomarkers in serum/plasma-MiR122 [ Time Frame: 10hours ]
    MiR122

  69. Experimental biomarkers in serum/plasma-MiR122 [ Time Frame: 20hours ]
    MiR122

  70. Experimental biomarkers in serum/plasma-GLDH [ Time Frame: 2hours ]
    GLDH

  71. Experimental biomarkers in serum/plasma-GLDH [ Time Frame: 10 hours ]
    GLDH

  72. Experimental biomarkers in serum/plasma-GLDH [ Time Frame: 20 hours ]
    GLDH

  73. Experimental biomarkers in serum/plasma-mitochondrial DNA [ Time Frame: 2hours ]
    mitochondrial DNA

  74. Experimental biomarkers in serum/plasma-mitochondrial DNA [ Time Frame: 10 hours ]
    mitochondrial DNA

  75. Experimental biomarkers in serum/plasma-mitochondrial DNA [ Time Frame: 20 hours ]
    mitochondrial DNA

  76. Experimental biomarkers in serum/plasma - CK18 [ Time Frame: 2 hours ]
    CK18

  77. Experimental biomarkers in serum/plasma - CK18 [ Time Frame: 10 hours ]
    CK18

  78. Experimental biomarkers in serum/plasma - CK18 [ Time Frame: 20 hours ]
    CK18

  79. Experimental biomarkers in serum/plasma-microRNA [ Time Frame: 2 hours ]
    microRNA

  80. Experimental biomarkers in serum/plasma-microRNA [ Time Frame: 10 hours ]
    microRNA

  81. Experimental biomarkers in serum/plasma-microRNA [ Time Frame: 20 hours ]
    microRNA

  82. Incidence of hepatotoxicity [ Time Frame: 2 hours ]
    Incidence of hepatotoxicity between 12hr NAC arm and individual PP100-01 + NAC treatment arms

  83. Incidence of hepatotoxicity [ Time Frame: 10 hours ]
    Incidence of hepatotoxicity between 12hr NAC arm and individual PP100-01 + NAC treatment arms

  84. Incidence of hepatotoxicity [ Time Frame: 20 hours ]
    Incidence of hepatotoxicity between 12hr NAC arm and individual PP100-01 + NAC treatment arms

  85. Duration of hospital stay [ Time Frame: 90days ]
    Days for the individual PP100-01 + NAC arms vs 12hr NAC arm

  86. Exploratory Secondary outcome - Hepatotoxicity [ Time Frame: 20hrs ]
    To determine the rate of occurrence of hepatotoxicity (defined by raised biochemical markers) in patients treated with PP100-01 and 12hr NAC administration regimens.

  87. Exploratory Secondary outcome - Anaphylactoid reactions [ Time Frame: 20hrs ]
    To compare the incidence of anaphylactoid reactions in the co-treatment and 12hr NAC regimens in APAP poisoned patients.

  88. Exploratory Secondary outcome - occurrence of hepatotoxicity [ Time Frame: 12hr ]
    To determine the occurrence of hepatotoxicity as determined at the end of the 12hr NAC administration regimen.

  89. Exploratory Secondary outcome - length of hospital stay [ Time Frame: 90days ]
    To measure length of hospital stay in patients receiving co-treatment and 12hr NAC treatment regimens.

  90. Exploratory Secondary outcome - ALT increase [ Time Frame: 10hr ]
    Proportion of patients with a 50% increase in ALT after 10h post-treatment with NAC, compared with the admission value

  91. Exploratory Secondary outcome - ALT>100 [ Time Frame: 10hr ]
    Proportion of patients with ALT>100 at 10h post-treatment with NAC

  92. Exploratory Secondary outcome INR>1.3 [ Time Frame: 10hr ]
    Proportion of patients with INR>1.3 at 10h post-treatment with NAC

  93. Exploratory Secondary outcome - APAP concentration >20mg/mL [ Time Frame: 20hrs ]
    Proportion of patients with paracetamol/acetaminophen (APAP) concentration > 20 mg/mL



Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Any patient with capacity admitted to hospital within 24 hrs either a single acute POD or more than one dose of paracetamol (staggered) and deemed to require treatment with NAC.
  2. Provision of written informed consent
  3. Males and females of at least 16 years of age

Exclusion Criteria:

  1. Patients that do not have the capacity to consent to participate in the study
  2. Patients detained under the Mental Health Act or deemed unfit by the Investigator to participate due to mental health.
  3. Patients with known permanent cognitive impairment
  4. Patients who are pregnant or nursing
  5. Patients who have previously participated in the study
  6. Unreliable history of POD
  7. Patients presenting after 24hrs of POD
  8. Patients who take anticoagulants (e.g. warfarin) therapeutically or have taken an overdose of anticoagulants
  9. Patients who, in the opinion of the responsible clinician/nurse, are unlikely to complete the full course of NAC e.g. expressing wish to self-discharge
  10. Prisoners
  11. Non-English speaking patients. (Study information material will only be produced in English in view of the known and stable demographic of the Edinburgh self-harm population).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03177395


Locations
United Kingdom
Royal Infirmary of Edinburgh
Edinburgh, City Of Edinburgh, United Kingdom, EH16 4SA
Sponsors and Collaborators
PledPharma AB
University of Edinburgh
NHS Lothian
Investigators
Principal Investigator: James Dear University of Edinburgh

Responsible Party: PledPharma AB
ClinicalTrials.gov Identifier: NCT03177395     History of Changes
Other Study ID Numbers: PP100-001
First Posted: June 6, 2017    Key Record Dates
Last Update Posted: June 5, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Drug Overdose
Substance-Related Disorders
Chemically-Induced Disorders
Acetaminophen
Acetylcysteine
N-monoacetylcystine
Edetic Acid
Pyridoxal Phosphate
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Antidotes
Anticoagulants
Calcium Chelating Agents
Chelating Agents
Sequestering Agents
Vitamin B Complex
Vitamins
Micronutrients