The StAmP Trial: A Proof of Principle, double blind, Randomised Placebo-Controlled, Multi Centre Trial of Statins to Ameliorate Early Onset Pre-eclampsia. ISRCTN: 23410175 EudraCT Number: 2009-012968-13 Sponsor Protocol Number: UCL 08/0350 StAmP Pharmacy Manual V1.1 14Jan2011 Page 1 of 11
TABLE OF CONTENTS 1. Pharmacy Responsibilities... 3 2. Trial IMP Description... 3 3. IMP Supply and Ordering... 3 4. IMP costs... 4 5. IMP labelling... 4 6. IMP Storage... 5 7. Route of Administration, Dosage, Dosage Regimen and Treatment Period... 5 8. Patient Randomisation... 6 9. Unblinding... 7 10. IMP Receipt... 7 11. IMP Accountability and Reconciliation... 8 12. IMP Return and Destruction... 9 13. Monitoring... 10 14. Archiving... 10 15. Reports/Correspondence... 10 StAmP Pharmacy Manual V1.1 14Jan2011 Page 2 of 11
1. Pharmacy Responsibilities A pharmacist must be named and must sign the site Trial Signature & Delegation Log, a copy of which is provided in section 3 of the Site File. The Site File is kept by the Principal Investigator. All personnel responsible for the receipt, storage, dispensation and destruction of trial medication must also sign this form. This form must also be co-signed by the site s Principal Investigator. Once complete, a copy of the form must be returned to the StAmP Trial office. The original must be retained in section 3 of the Site File. New site personnel accepting responsibilities can then be added to the form if required. Please ensure that the StAmP Trial office is informed of any changes in the contact details for the responsible pharmacist. Should the responsible pharmacist change, the Trial Signature & Delegation Log must be updated and forwarded to the StAmP Trial office. 2. Trial IMP Description The investigation medicinal product (IMP) is pravastatin, as 40mg pravastatin sodium as a capsule. The most recent Summary of Product Characteristics for pravastatin can be found at http://emc.medicines.org.uk. Blinding of Pravastatin 40mg tablets will be carried out by the process of over-encapsulation. One entire tablet will be placed inside a size 00 opaque hard gelatine capsule. A Lactose / 1% Magnesium Stearate blend will be added to stop the tablet rattling inside the capsule. The placebo will be a placebo capsule, encapsulated in the same format as the IMP to be identical in colour, shape and weight. A matching size 00 opaque hard gelatine capsules will be filled with Lactose / 1% Magnesium Stearate blend alone to produce placebo capsules for the study. 3. IMP Supply and Ordering The study drug will be supplied, packaged and distributed by Bilcare (UK) Ltd using their clinical trial drug distribution procedures. Bilcare will procure Pravastatin inspecting the certification of the IMP supplied by the manufacturer (Teva Ltd) and retaining one original blister pack per batch as reference. Bilcare will overencapsulate the IMP and placebo and package accordingly. Each treatment pack will consist of a resistant tamper evident container and will contain 28 capsules for use by an individual subject only. A pack MUST NOT be shared by two or more subjects. Container dimensions are approximately 8 x 5 x 5 cm. Pharmacies should provide full details of where the drug is to be delivered to and a contact name and number for the courier to call in the event of any problems. 3.1. Pravastatin and Placebo Supply At study initiation, Birmingham Clinical Trials Unit will arrange an initial supply of Pravastatin and placebo to be automatically shipped by Bilcare (UK) Ltd to the pharmacist at the trial site. Each trial site will receive an initial supply of 8 treatment packs (4 of Pravastatin and 4 of Placebo). (The total number may vary depending on anticipated recruitment rates at the trial centre.) Box dimensions are approximately 8 x 5 x 5 cm. StAmP Pharmacy Manual V1.1 14Jan2011 Page 3 of 11
Bilcare will provide the QP release service prior to delivery under the requirements of the Medicines for Human Use (Clinical Trials) Regulations 2004 and the amendments. 3.2. Trial Drug Re-supply Re-supply of pravastatin and placebo will be managed manually. Birmingham Clinical Trials Unit (BCTU) will be informed when a patient has been randomised to the study. This information will be tracked to allow calculation of available supplies on site. This will prompt BCTU to verify that pravastatin and placebo supply levels at site are sufficient. If supply quantities are not adequate, BCTU will contact Bilcare accordingly. In addition, if it is noticed at site that supplies are getting low and additional trial drug supply is needed, please contact the BCTU who will be able to request a resupply. A re-supply will consist of 8 treatment packs (4 of Pravastatin and 4 of Placebo). (The total number may vary depending on anticipated recruitment rates at the trial centre.) Bilcare will provide the QP release service prior to delivery under the requirements of the Medicines for Human Use (Clinical Trials) Regulations 2004 and the amendments. It is assumed that for the majority of participants, delivery will occur within 28 days of randomisation. However, in case some deliveries occur later than 28 days post-randomisation, continuation trial drug packs will be available. Should it be considered likely, at 21 days post-randomisation,that the pregnancy will continue beyond 28 days, the Principal Investigator or other clinical investigator must contact BCTU to arrange have a continuation pack, containing 28 capsules to be labelled and dispatched to the centre. Should a treatment pack be lost or damaged post-randomisation, a replacement drug treatment pack can be obtained by the pharmacist by the same mechanism. The reason must be documented on the StAmP Drug Accountability Log (see section 11) and fully investigated if appropriate. 4. IMP costs The trial drug will be provided free of charge. The cost of Pravastatin and placebo is covered by the StAmP Trial. 5. IMP labelling The drug will be labelled by Bilcare in compliance with regulatory requirements (Annex 13) and will have been submitted to the competent authority as part of the Clinical Trial Authorisation process, so should be consistently applied. Any addition or modification to the label apart from the variable data must be authorized by the Sponsor. Pravastatin/ Placebo bottle labels for the study are displayed below. (Note: that V denotes variable information). StAmP Pharmacy Manual V1.1 14Jan2011 Page 4 of 11
6. IMP Storage 6.1. Storage Conditions Pravastatin and placebo should be stored in a dry place at a temperature of 15 o - 30 o C. 6.2. Stability of trial drugs The shelf life for pravastatin and placebo is 36 months when stored at 15 o - 30 o C. No IMP can be dispensed beyond the expiry date. 6.3. Temperature Deviation Pravastatin and placebo should be stored 15 o - 30 o C. Provision must be in place to store the IMP within the permitted temperature range. Temperature must be monitored regularly. Ideally, a continuing electronic monitoring system (24/7) is expected. However it is acceptable to use a well maintained system of max min thermometer recording at least once per working day. Diligence is expected in checking that at the time of dispensing, the IMP has always been stored in the permitted range. Whichever system is adopted the equipment must be regularly calibrated and a certificate of recalibration be available to the Sponsor or StAmP Trial Office at least once a year. Temperature logs should be maintained at all times. Temperature logs must be available for inspection by the monitoring team, when requested at monitoring visits. Should there be a deviation in the storage temperature of the trial drug, it must be immediately quarantined. The StAmP trials office should also be notified immediately of the deviation and sites will be instructed accordingly. The deviation must be recorded on the Temperature Deviation Form, copies of which are provided in section 4 of the Pharmacy Site File. The Investigator should be immediately contacted and eventual IMP already dispensed recalled. Patient safety should be managed according to GCP. 7. Route of Administration, Dosage, Dosage Regimen and Treatment Period A single capsule must be taken as once daily in the evening, orally with or without food. On the day of randomisation, the first dose should be given that evening. If a patient is randomised too late in the evening, the first dose may be given the following evening. Treatment should continue daily in the evening until the pregnancy is ended. StAmP Pharmacy Manual V1.1 14Jan2011 Page 5 of 11
If it is clear that the tablet has not been absorbed, i.e. vomited up within 2 hours, then they should have another tablet. If the tablet is missed by less than 18 hours, a further tablet should be taken. 8. Patient Randomisation Pharmacy notification of patient randomisation will be sent immediately by email following randomisation from the Birmingham Clinical Trials Unit (BCTU) to the pharmacy responsible for dispensing the trial drug to the patient. The email notification will confirm the following details: Patient initials Date of Birth Hospital Number Date of Randomisation Trial Number Bottle Number The bottle number provided will correspond to a drug treatment pack available in the hospital pharmacy. On receipt of randomisation notification, the pharmacist will prepare the drug treatment pack for dispensing. The treatment pack will contain 28 capsules for use by one participant. The pharmacist should complete the pack label with the following details before dispensing: Patient Initials Patient Trial Number Investigator Site Date of Dispensing Randomisation acknowledgement emails should be filed in section 5 of the Pharmacy Site File. 8.1 Allocation of Treatment in event of a Manual Paper Randomisation In the unlikely event of the computer system being unavailable to perform the randomisation, a manual paper randomisation will be performed. In such cases, the Clinical Investigator/ Research Midwife will notify the Pharmacist that a manual randomisation is required. The Pharmacist should then randomly select any available treatment pack. The Pharmacist should notify the Clinical Investigator/ Research Midwife of the selected bottle number. They will need to relay this information to the StAmP Trial Office. The expiry date on pack allocated manually must be checked to ensure that it is not within 1 month of dispensing. Birmingham Clinical Trials Unit (BCTU) will send a fax with paper randomisation confirmation. The pharmacist should complete the pack label as above before dispensing. Once computer system is available again, a randomisation acknowledgement email will be sent. These should be filed in section 5 of the Pharmacy Site File as above. StAmP Pharmacy Manual V1.1 14Jan2011 Page 6 of 11
9. Unblinding Participants, investigators, research midwives and other attending clinicians will remain blind to the trial drug allocation for the duration of the trial and will not have access to the trial number-treatment allocation code for the duration of the interventional phase of the trial. Should a serious, adverse event occur, management and care of the women should be initiated as though the woman was taking pravastatin. Cases that are considered serious, unexpected and possibly, probably or definitely related (i.e. possible SUSARs - see Section 7 of the protocol) should be unblinded only at the Trial Office by the StAmP Trial Coordinator. The attending clinician and local PI will not be made aware of the actual trial drug. Investigators and research midwives should remain blind to drug allocation as far as possible, however if the drug allocation is required for the medical management of particular patients, clinicians should contact the StAmP Trial Office. Alternatively, use the online StAmP code-break system. This service will be available 24 hours a day, 7 days a week. FOR UNBLINDING Online https://www.trials.bham.ac.uk/stamp (You will need your username and password) OR Contact the StAmP Trial Office on Tel: 0121 415 9112 (office hours only) 10. IMP Receipt Each shipment will contain one Packing Slip and Shipment Receipt Confirmation. The pharmacist must sign the receipt confirmation verifying the quantity and condition of the supplies received. The pharmacist must then fax a copy of the signed receipt confirmation to Bilcare to the number indicated AND fax a copy to the StAmP Trial Office on 0121 415 9136. Please retain all transmission forms. The Pharmacist must retain the original signed confirmation in section 4 of the Pharmacy File. The Packing Slip and Shipment Receipt Confirmation is required to document that the site received the trial drug in good condition and in the quantity noted. When a shipment is received, please inventory, inspect and verify the contents of the shipment for the following: Ensure the shipment is received free from damage. Ensure that the drug shipped is what is recorded on the form. Make sure that total quantity received is as listed on the form. Verify that the tamper evident seal is intact on the individual bottles. Conduct a thorough inspection of the shipment and mark the condition of drug as it was received. If applicable, contact Bilcare immediately for any problems relating to the shipment of trial drug. Provide the problem information in the comments area provided on the form. If everything is in order, please sign and date the form. ALL consignments of trial drug, whether in good condition or damaged, MUST be confirmed. Retain the original signed Packing Slip and Shipment Receipt Confirmation in the Pharmacy File. If there is a problem with the shipment, contact Bilcare immediately notifying them of the problem. Provide the problem information in comments area provided on the Packing Slip and Shipment StAmP Pharmacy Manual V1.1 14Jan2011 Page 7 of 11
Receipt Confirmation and fax all pages of the letter on the day you receive the product to the number indicated on the form. 11. IMP Accountability and Reconciliation Trial Drug Accountability Logs are provided in section 4 of the Pharmacy Site file. Accurate records of all drugs dispensed must be maintained. These records must be available for inspection by representatives of the StAmP Trial Office or UCL as sponsor at any time. Drug supplies are to be used only in accordance with this protocol and under the supervision of the Investigator. The study pharmacist should ensure that a clear log of the investigational product dispensed is maintained throughout the study. We would like you to use our trial specific forms. Upon receipt of trial drugs, complete the StAmP Drug Accountability Log with the relevant information about number of packs, batch number, expiry date and increasing the New Total in Stock by the number of packs that have been received. When dispensing drugs to a patient, ensure that the patient details are completed, and the New Total in Stock is reduced by the amount dispensed. Drugs returned to the pharmacy after dispensing must not be re-used. Keep medication returned from patients separate from trial stocks. Complete the StAmP Drug Accountability Log by ticking the Return box and filling in the information about number of capsules returned, batch and expiry date but DO NOT add the number returned to the New Total in Stock. Returned medication must be destroyed in a documented manner. To document destruction, complete the StAmP Drug Accountability log by ticking the Destruction box, and filling in the information about the number of capsules, batch and expiry date but DO NOT deduct the number destroyed from the New Total in Stock. Record any information relevant to the destruction in the comments section e.g. Returned medication destroyed as per local policy. When there is a requirement to destroy drugs from stock e.g. expired or damaged stock, document the destruction on the StAmP Drug Accountability Log by ticking the Destruction box, and filling in the information about the number of packs, batch and expiry date. Remember to deduct the number destroyed from the New Total in Stock. Record any information relevant to the destruction in the comments section e.g. Expired stock medication destroyed with permission of the Sponsor as per local policy. Use continuation sheet if first sheet is full. Ensure to add page number to the footer. Ensure any completed logs are ultimately stored in the Investigator Site File and copies are forwarded to the StAmP Trial Office as per instruction. Note that during the trial, the trial completed logs may be stored in the Pharmacy File. Any discrepancies must be documented and subsequently reported to the StAmP Trial Office immediately. These inventories must be made available for inspection by authorized representative(s) of UCL as sponsor, the StAmP Trial Office, and regulatory agency inspector(s). The Investigator is responsible for the accountability of all used and unused trial supplies. StAmP Pharmacy Manual V1.1 14Jan2011 Page 8 of 11
Drug accountability records must be completed by the pharmacist or designee and kept up-to-date. Investigational product accountability/reconciliation should be performed regularly. 12. IMP Return and Destruction Returned and unused packs of trial drug must be destroyed according to hospital procedures and be properly accounted for in the StAmP Drug Accountability Log filed in section 4 of the Pharmacy Site File as detailed above in Section 11. Return of used investigational product should be managed on a regular basis to prevent a back-log of used trial drug at site pharmacy. The timing of returns is more often than not dictated by the site s storage capabilities. Note: Trial drug can only be destroyed on site if the site has a documented procedure and the sponsor or the StAmP Trial Office has given appropriate approval in writing. A copy of the documented procedure for destruction will need to be provided to the StAmP Trial Office and a copy should be retained in the Pharmacy File. 12.1. IMP return and destruction at Bilcare When it is not possible for the site to destroy used or unused trial drug on site, it can be returned to Bilcare for destruction. The trial pharmacist should ensure a clear log is kept on the StAmP Drug Accountability Log. When there is a requirement to return used trial drug to Bilcare, document the return by ticking the Return to Bilcare box, and filling in the information about the number of capsules, batch and expiry date but DO NOT deduct the number returned from the New Total in Stock. Record any information relevant to the return in the comments section e.g. Returned medication returned to Bilcare for destruction. When there is a requirement to return drugs from stock e.g. expired or damaged stock drug to Bilcare for destruction, document the return by ticking the Return to Bilcare box, and filling in the information about the number of packs, batch and expiry date. Remember to deduct the number destroyed from the New Total in Stock. Record any information relevant to the return in the comments section e.g. Expired stock medication returned to Bilcare with permission of the Sponsor as per local policy. A Return of Trial Drug for Destruction Form must also be completed and included in the shipment of used and unused investigational product to Bilcare. Return of Trial Drug for Destruction Forms are filed in section 4 of the Pharmacy Site File. Ensure name of the Principal Investigator, Site and name of the Lead Pharmacist is correctly detailed. Enter the complete batch number, expiry date and bottle number When returning used drug after dispensing, enter the number of capsules returned for destruction When returning unused drug e.g. expired or damaged stock, check the unused column The completed form is to be signed and dated by the individual verifying and returning the product. A copy will be returned to Bilcare enclosed with the return shipment, and the original remains at the site in the Pharmacy Binder. StAmP Pharmacy Manual V1.1 14Jan2011 Page 9 of 11
A Bilcare Collection Request Form must be completed and faxed to Bilcare to initiate a collection. Enter University of Edinburgh as Customer Reference Number Enter StAmP as Study Reference Ensure complete details on contact at pick up and collection address details. On receipt of the Collection Request Form, Bilcare will contact pharmacy contact to arrange the collection date and details. At the end of the study, the Final Investigational Product Reconciliation Statement must be completed and provided to the StAmP Trial Office. 13. Monitoring The StAmP Trial will be monitored by the StAmP Trial Coordinator from the StAmP Trial Office. Monitoring may also be performed by representatives of UCL as the Sponsor or representatives of the regulatory authorities. 14. Archiving The Pharmacy Site file for the StAmP Trial should be archived along with all the essential trial documentation and source records (e.g. signed Consent Forms, Investigator and patients hospital notes, copies of Case Report Forms etc) at site and should be securely retained for at least 5 years (but ideally not less than 15 years) after the end of the trial. Participating sites will be sent a letter specifying the permissible disposal date. 15. Reports/Correspondence Please file the Monitor Visit Report for each monitoring visit in section 7 of the Pharmacy site File. The Monitor Visit Report documents activities performed and issues noted by a Monitor during an on-site monitoring visit. Please file follow up letters from monitoring visits also in section 7 of the Pharmacy Site File. Please file any general correspondence regarding the StAmP Trial in section 7 of the Pharmacy Site File. Thank you for your valued support of the StAmP Trial StAmP Pharmacy Manual V1.1 14Jan2011 Page 10 of 11
Should you have any queries or require further information, please contact: Chief Investigator Dr David Williams University College London Hospital Institute for Women s Health 74 Huntley Street London WC1E 6DD : 020 7679 6948 : d.j.williams@ucl.ac.uk Sponsor University College London Contact Temi Giwa University College London Hospital Research and Development Office 1 st Floor, Maple House, Ground Floor Rosenheim Wing, 25 Grafton Way London WC1E 6DB : 020 7679 6488 : t.giwa@ucl.ac.uk StAmP Trial Office Birmingham Clinical Trials Unit (BCTU) Trial Coordinator Miss Alex Furmston Birmingham Clinical Trials Unit Robert Aitken Institute University of Birmingham Edgbaston Birmingham B15 2TT : 0121 415 9112 FAX: 0121 415 9136 : a.t.furmston@bham.ac.uk StAmP Pharmacy Manual V1.1 14Jan2011 Page 11 of 11