WO2021200651A1 - コロナウイルス感染症治療剤 - Google Patents
コロナウイルス感染症治療剤 Download PDFInfo
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- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
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- 229940127234 oral contraceptive Drugs 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
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- 229960004919 procaine Drugs 0.000 description 1
- CWCXERYKLSEGEZ-KDKHKZEGSA-N procalcitonin Chemical compound C([C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(O)=O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCSC)NC(=O)[C@H]1NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@@H](N)CSSC1)[C@@H](C)O)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 CWCXERYKLSEGEZ-KDKHKZEGSA-N 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- RWWYLEGWBNMMLJ-MEUHYHILSA-N remdesivir Drugs C([C@@H]1[C@H]([C@@H](O)[C@@](C#N)(O1)C=1N2N=CN=C(N)C2=CC=1)O)OP(=O)(N[C@@H](C)C(=O)OCC(CC)CC)OC1=CC=CC=C1 RWWYLEGWBNMMLJ-MEUHYHILSA-N 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000036387 respiratory rate Effects 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to a therapeutic agent for coronavirus infection containing 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (generic name: favipiravir; hereinafter referred to as compound A) or a salt thereof as an active ingredient.
- Non-Patent Document 1 The new coronavirus (SARS-CoV-2) (Non-Patent Document 1), which was first reported in China at the end of 2019, is an RNA virus belonging to the family Coronaviridae of the order Nidovirales (Non-Patent Document 2). When infected with this virus, it is accompanied by acute respiratory symptoms such as fever, cough, and dyspnea (Non-Patent Document 1), and when it worsens, pneumonia develops. As of March 22, 2020, more than 290,000 SARS-CoV-2 infection (COVID-19) cases and more than 12,000 deaths have been reported worldwide, and 1046 COVID-19 cases in Japan. There are reports of patients, of which 36 deaths have been confirmed (Non-Patent Document 3).
- Compound A is an antiviral drug created by FUJIFILM Toyama Chemical Co., Ltd. (formerly Toyama Chemical Co., Ltd.), and has the indication of "new or re-emerging influenza virus infection (however, other anti-influenza virus drugs).
- T-705RTP triphosphory oxidant
- a treatment method for coronavirus infection has not been established, and it is necessary to develop a therapeutic agent for coronavirus infection at an early stage.
- An object to be solved by the present invention is to provide a therapeutic agent for coronavirus infection and a method for treating coronavirus infection.
- a coronavirus infection can be treated by administering compound A or a salt thereof to a coronavirus infection patient, and have completed the present invention.
- the coronavirus infection therapeutic agent according to [1] wherein the patient is a patient with a new type of coronavirus infection.
- B Compound A or a salt thereof for treating a coronavirus infection, which is administered to a patient with non-severe pneumonia.
- C A method for treating a coronavirus infection in which Compound A or a salt thereof is administered, which is administered to a patient with non-severe pneumonia.
- D Use of Compound A or a salt thereof for the manufacture of a therapeutic agent for coronavirus infection to be administered to patients with non-severe pneumonia.
- Coronavirus infection can be treated by administering Compound A or a salt thereof to a coronavirus infection patient with non-serious pneumonia.
- the numerical range indicated by using “-" in the present specification means a range including the numerical values before and after "-" as the minimum value and the maximum value, respectively.
- Compound A means 6-fluoro-3-hydroxy-2-pyrazinecarboxamide.
- salts in the basic group include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitrate and sulfuric acid; formic acid, acetic acid, citrate, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartrate, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Can be mentioned.
- Salts in acidic groups include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N- Nitrogen-containing substances such as dimethylaniline, N-methylpiperidin, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine, N, N'-dibenzylethylenediamine and meglumine. Examples include salts with organic bases.
- preferred salts include pharmacologically acceptable salts, and more preferred salts include salts with sodium or meglumine.
- isomers eg, optical isomers, geometric isomers and tautomers, etc.
- the present invention includes all of these isomers and also hydrates. It includes solvates and all crystalline forms.
- coronavirus used herein is an RNA virus belonging to the family Coronaviridae of the order Nidovirales. Infectious diseases caused by coronavirus are coronavirus infections.
- the "new coronavirus” is a new type of coronavirus that has been newly identified and reported among the coronaviruses, and examples thereof include SARS-CoV-2 reported at the end of 2019. Infectious diseases caused by SARS-CoV-2 are also called COVID-19.
- the "new coronavirus” naturally includes known variants and strains of coronavirus.
- Treatment means reducing or ameliorating one or more symptoms resulting from a particular disease in which the subject is affected, as well as delaying the progression of the disease.
- it means reducing or ameliorating symptoms such as fever, cough, pneumonia, body temperature, percutaneous arterial oxygen saturation (SpO 2 ), and chest image. It means amelioration of findings or negative coronavirus.
- the patient to whom Compound A or a salt thereof is administered is preferably a patient with non-severe pneumonia.
- the non-serious pneumonia means pneumonia to the extent that hypoxemia that requires oxygen therapy is not observed.
- Compound A or a salt thereof used in the present invention can be produced by a method known per se or by appropriately combining them. For example, it can be manufactured by the method described in International Publication No. 00/10569.
- Compound A contains tautomers 6-fluoro-3-oxo-3 and 4-dihydro-2-pyrazinecarboxamide.
- the compound A or a salt thereof used in the present invention is an excipient, a binder, a disintegrant, a disintegration inhibitor, a caking / adhesion inhibitor, a lubricant, an absorption / adsorption carrier, a solvent, a bulking agent, and isotonic.
- Agents solubilizers, emulsifiers, suspending agents, thickeners, coating agents, absorption promoters, gelation / coagulation accelerators, photostabilizers, preservatives, moisture barriers, emulsification / suspension / dispersion stabilization
- Various pharmaceutical additives such as agents, color inhibitors, deoxidizers / antioxidants, flavoring / deodorants, colorants, foaming agents, defoamers, painkillers, antistatic agents, buffers / pH adjusters, etc.
- oral preparations tablets, capsules, powders, granules, fine granules, rounds, suspensions, emulsions, liquids, syrups, etc.
- injections eye drops
- nasal or transdermal preparations It can be a pharmaceutical product such as.
- an oral preparation or an injection preparation is preferable, an oral preparation is more preferable, and a tablet is further preferable.
- the above-mentioned drug is formulated by a usual method.
- the method of administering Compound A is not particularly limited, but is appropriately determined according to the form of the pharmaceutical product, the age of the patient, gender and other conditions, and the degree of symptoms of the patient.
- the 50% effect concentration (EC50) of Compound A on SARS-CoV-2 using Vero E6 cells was 61.88 ⁇ M (Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020; 30: 269-71.). This corresponds to 9.72 ⁇ g / mL.
- the dose of Compound A is appropriately selected depending on the usage, age, sex, disease form, other conditions, etc. of the patient.
- the dose of Compound A is 10 to 5000 mg, or preferably 200.
- ⁇ 2400 mg can be administered once daily or in divided doses.
- Compound A may be administered in multiple doses or in a single dose until the desired therapeutic effect is achieved. Administration is typically monitored and can be repeated as needed.
- 1000 to 2400 mg of Compound A may be administered to an adult twice a day (1st day) and 400 to 1200 mg twice a day (after the 2nd day).
- 1600 mg of compound A should be administered twice daily (1st day), 600 mg twice daily (after the 2nd day), and for adults, 1800 mg of compound A should be administered 2 times daily. It is preferable to administer 800 mg twice a day (after the second day) once (1st day), and 1800 mg of compound A twice a day (1st day) and 800 mg twice a day (2nd day). After that) it is more preferable to administer. As for the dosing interval of twice a day, it is preferable to administer the second dose at least 4 hours after the first dose, and more preferably to administer the second dose at an interval of 6 hours or more.
- the administration period is appropriately determined according to the transition of symptoms, but for example, up to 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, You can choose from 16 days, 17 days, 18 days, 19 days, 20 days, 21 days and 22 days. A maximum of 10 days, 13 days, 14 days and 22 days is preferable, and a maximum of 13 days and 14 days is more preferable.
- administration of Compound A or a salt thereof can include combination drugs and / or combination therapies.
- standard treatment for pneumonia is the "Guide for the treatment of new coronavirus infection (COVID-19), No. 1", which was announced on March 17, 2020 by the Japan Ministry of Health, Labor and Welfare's New Coronavirus Infection Control Promotion Headquarters.
- the treatment described in "3 Treatments” of the edition specifically, "If a patient with suspected infection is clinically diagnosed with pneumonia, the antibacterial drug is empiricly started without waiting for the result of the pathogen diagnosis. It is desirable to do this. Be careful not to overfill the infusion and start inhaling oxygen as needed.
- a drug having an antiviral effect against ribavirin or coronavirus can be included.
- the drug having an antiviral action against the coronavirus include the following drugs a) to e). a) Hydroxychloroquine sulfate, chloroquine phosphate b) Lopinavir / ritonavir combination drug c) Ciclesonide d) Nafamostat mesylate e) Camostat mesylate
- Test Example 1 Adaptive single-blind, randomized, multicenter, collaborative study evaluating the efficacy and safety of Compound A in COVID-19 patients with non-severe pneumonia [Method] 1.
- Clinical trial design 1.1 Types of clinical trials Validating trials (Phase III)
- Target number of patients The number of patients to be included is 96 (64 in compound A group, 32 in control group).
- Subject 2.1 Subject COVID-19 patients with non-severe pneumonia
- Dosage and administration period 4.1 Dosage and administration (1) Dosage In addition to the standard treatment, the following doses of the investigational drug will be administered to each administration group.
- Compound A group Compound A 1800mg x 2 times / day x 1 day + 800mg x 2 times / day x 13 days (maximum)
- Control group Compound A Placebo 9 tablets x 2 times / day x 1 day + 4 tablets x 2 times / day x 13 days (maximum)
- Tablet A (containing 200 mg of compound A) is orally administered 9 tablets twice a day on the first day, and 4 tablets twice a day on the second and subsequent days for a maximum of 13 days.
- Tablet B (placebo containing no compound A) is orally administered 9 tablets twice a day on the first day and 4 tablets twice a day on the second and subsequent days for a maximum of 13 days.
- the second dose should be given at least 4 hours after the first dose of the investigational drug.
- the maximum administration period is 14 days.
- Clinical Trial Implementation Procedure The clinical trial will be conducted according to the following procedure. (1) Confirmation of selection / exclusion criteria, explanation of clinical trial, acquisition of consent, implementation of observation / examination before start of administration (2) Registration of patients (incorporation of clinical trial) (3) Allocation to treatment (4) Prescription of investigational drug, start of administration (5) Prescribed observation / test implementation, evaluation / judgment (6)
- Following-up survey (1) Confirmation of selection / exclusion criteria, explanation of clinical trial, acquisition of consent, implementation of observation / examination before start of administration (2) Registration of patients (incorporation of clinical trial) (3) Allocation to treatment (4) Prescription of investigational drug, start of administration (5) Prescribed observation / test implementation, evaluation / judgment (6)
- SARS-CoV-2 reaches the state d) and maintains it for 12 hours or more.
- Body temperature 37.4 ° C or less (do not use measurements within 4 hours after using antipyretic analgesics)
- SpO 2 96% or more (without oxygen therapy)
- Chest imaging findings improvement from worst d)
- Criteria for secondary endpoints a) Time until SARS-CoV-2 disappears The time from the start of study drug administration until SARS-CoV-2 becomes "negative” is the time until SARS-CoV-2 disappears. Evaluate as time. b) Duration of each symptom / finding of body temperature, SpO 2 and chest imaging findings For each symptom / finding of body temperature, SpO 2 and chest imaging findings, from the start of administration of the investigational drug, 1) a) to c) above Evaluate the time until the condition is reached and maintained for 2 days or more (48 hours or more as a guide) as the duration for each symptom / finding.
- the median was about 3 days earlier than in the control group, and the time required for 75% of patients to improve was 15.6 days in the compound A group, whereas in the control group, it was observed for 28 days. , Still more than 25% of patients did not improve. It was statistically significantly confirmed that the therapeutic effect of compound A group was higher than that of the control group. In addition, no clinical problems were found in the safety of compound A group.
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Abstract
Description
[1]
非重篤な肺炎を合併した患者に対して投与される、6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミド又はその塩を有効成分として含有するコロナウイルス感染症治療剤。
[2]
患者が、新型コロナウイルス感染症患者である、[1]に記載のコロナウイルス感染症治療剤。
[3]
患者が、以下(1)~(3)の基準をすべて満たす患者である、[1]又は[2]に記載のコロナウイルス感染症治療剤。
(1)コロナウイルス陽性である
(2)胸部画像で肺病変を認める
(3)37.5℃以上の発熱を認める
[4]
6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミドとして、1000~2400mgを1日2回(1日目)、400~1200mgを1日2回(2日目以降)投与される、[1]~[3]いずれか1に記載のコロナウイルス感染症治療剤。
[5]
6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミドとして、1800mgを1日2回(1日目)、800mgを1日2回(2日目以降)投与される、[1]~[3]いずれか1に記載のコロナウイルス感染症治療剤。
[6]
6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミド又はその塩を14日間投与する、[1]~[5]いずれか1に記載のコロナウイルス感染症治療剤。
(a)コロナウイルス感染症を治療するための、化合物A又はその塩を含有する医薬組成物であって、非重篤な肺炎を合併した患者に投与される、医薬組成物。
(b)コロナウイルス感染症を治療するための、化合物A又はその塩であって、非重篤な肺炎を合併した患者に投与される、化合物A又はその塩。
(c)化合物A又はその塩を投与するコロナウイルス感染症の治療方法であって、非重篤な肺炎を合併した患者に投与する、コロナウイルス感染症の治療方法。
(d)非重篤な肺炎を合併した患者に投与されるコロナウイルス感染症治療剤の製造のための、化合物A又はその塩の使用。
本明細書において特に断らない限り、各用語は次の意味を有する。
塩基性基における塩としては、たとえば、塩酸、臭化水素酸、硝酸及び硫酸などの鉱酸との塩;ギ酸、酢酸、クエン酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、酒石酸、アスパラギン酸、トリクロロ酢酸及びトリフルオロ酢酸などの有機カルボン酸との塩;ならびにメタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、メシチレンスルホン酸及びナフタレンスルホン酸などのスルホン酸との塩が挙げられる。
上記薬剤は、通常の方法により製剤化される。
Vero E6細胞を用いたSARS-CoV-2に対する化合物Aの50%効果濃度(EC50)は61.88 μMであった(Wang M、 Cao R、 Zhang L、 Yang X、 Liu J、 Xu M、 et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30:269-71.)。これは9.72 μg/mLに相当する。けれども、前記文献の公開当時には、実際の患者に投与した場合における効果は予想できなかった。
化合物Aの投与量は、用法、患者の年齢、性別、疾患の形態、その他の条件などに応じて適宜選択されるが、例えば、成人に対して、化合物Aとして、10~5000mg又は好ましくは200 ~2400mgが1日1回又は数回に分割して投与され得る。化合物Aは、所望の治療効果が達成されるまで複数回の投薬又は単回で投与され得る。投与は、典型的には監視され、必要に応じて繰り返し投与することができる。
本発明においては、成人に対して、化合物Aとして1000~2400mgを1日2回(1日目)、400~1200mgを1日2回(2日目以降)投与すればよい。成人に対して、化合物Aとして1600mgを1日2回(1日目)、600mgを1日2回(2日目以降)投与すること、及び成人に対して、化合物Aとして1800mgを1日2回(1日目)、800mgを1日2回(2日目以降)投与することが好ましく、化合物Aとして1800mgを1日2回(1日目)、800mgを1日2回(2日目以降)投与することがより好ましい。
1日2回の投与間隔は、1回目の投与から少なくとも4時間以上の間隔を空けて2回目を投与することが好ましく、6時間以上の間隔を空けて2回目を投与することがより好ましい。
投与期間は、症状の推移により適宜決定されるが、例えば、最長5日間、6日間、7日間、8日間、9日間、10日間、11日間、12日間、13日間、14日間、15日間、16日間、17日間、18日間、19日間、20日間、21日間及び22日間から選択できる。最長10日間、13日間、14日間、22日間が好ましく、最長13日間、14日間がより好ましい。
薬を投与する.」又はこれに準じた処置を意味する。また、酸素療法を含むことができる。さらに、インターフェロン アルファ製剤、リバビリン又はコロナウイルスに対して抗ウイルス作用を有する薬剤の投与を含むこともできる。コロナウイルスに対して抗ウイルス作用を有する薬剤としては、例えば以下a)~e)の薬剤が挙げられる。
a)ヒドロキシクロロキン硫酸塩、リン酸クロロキン
b)ロピナビル・リトナビル配合剤
c)シクレソニド
d)ナファモスタットメシル酸塩
e)カモスタットメシル酸塩
[方法]
1.治験デザイン
1.1 治験の種類
検証的試験(第III相)
アダプティブ、単盲検、ランダム化、多施設共同比較試験
[化合物A群]
標準治療+化合物A1800mg × 2回/日× 1日間+ 800mg × 2回/日× 13日間(最長)
[コントロール群]
標準治療+化合物Aプラセボ9錠× 2回/日× 1日間+ 4錠× 2回/日× 13日間(最長)
1.4.1 有効性の主要評価項目
体温、SpO2、胸部画像所見の軽快及びSARS-CoV-2が陰性化するまでの時間
(1)7ポイントスケールによる患者状態の推移
(2)SARS-CoV-2ゲノム量の推移
(3)SARS-CoV-2消失までの時間
(4)体温、SpO2及び胸部画像所見の各症状・所見別持続時間
(5)臨床症状・所見の推移
(6)バイタルサインの推移
(7)National Early Warning Score(NEWS)の推移
(8)Day 4、7、10、13、16、19、22、25、28の胸部画像所見の軽快率
(9)補助的酸素療法を必要とした患者の割合及び平均施行期間
(10)機械的換気療法を必要とした患者の割合及び平均施行期間
(11)白血球数、ヘモグロビン、血小板数、クレアチニン、血糖、総ビリルビン、ALT及びASTの経時推移
(1)有害事象
(2)臨床検査値
(3)バイタルサイン
(4)12誘導心電図
組入れ患者数として96名(化合物A群64名、コントロール群32名)
2.1 対象
非重篤な肺炎を合併したCOVID-19患者
(1)年齢:20~74歳(同意取得時)
(2)性別:不問
(3)外来・入院:入院
(4)患者の登録時に、下記1)、2)、3) の基準をすべて満たす患者
1) 鼻咽頭ぬぐい液、鼻腔吸引液、気道吸引液などの気道からの検体からRT-PCR(reverse transcription-polymerase chain reaction)検査などでSARS-CoV-2陽性となった患者
2) 胸部画像で肺病変を認める患者
3) 37.5°C以上の発熱を認める患者
(5)妊娠可能な女性患者を対象とする場合、治験薬投与開始前の妊娠検査で陰性を確認した患者
(6)本治験の内容を理解し、本人から文書同意取得が可能な患者
(1)発熱(37.5°C以上)後10日以上経過した患者
(2)発熱(37.5°C以上)後9日以内に、インターフェロンアルファ製剤、SARS-CoV-2に対して抗ウイルス作用が報告されている薬剤(ヒドロキシクロロキン硫酸塩、リン酸クロロキン、ロピナビル・リトナビル配合剤、シクレソニド、ナファモスタットメシル酸塩、カモスタットメシル酸塩)を使用した患者
(3)本感染エピソードがSARS-CoV-2感染の再発又は再感染の患者
(4)酸素療法なしの状態でSpO2が95%未満の患者
(5)治験薬投与開始前のプロカルシトニン値が上昇し、細菌感染症の合併が疑われる患者
(6)治験薬投与開始前の(1→3)-β-D-グルカン値が異常値を示し、真菌感染症の合併が疑われる患者
(7)治験薬投与開始前のNT-proBNP(N-terminal pro-brain natriuretic peptide)値が400 pg/mL以上(又はBNP値が100 pg/mL以上)の、うっ血性心不全の合併が疑われる患者
(8)Child-Pugh分類でグレードCに相当する重度肝機能障害を有する患者
(9)透析を必要とする腎機能障害患者
(10)見当識障害などの意識障害を認める患者
(11)妊婦又は妊娠している可能性のある患者
(12)治験薬投与開始から終了7日後までの間に、経口避妊薬、子宮内装具又はバリア法(ペッサリー、コンドーム)などの機械的避妊具を使用、及びそれらを組み合わせるなどの方法で避妊することに同意できない女性患者
(13)上記(12)に記載した避妊法を用いて避妊することに同意できないパートナーがいる男性患者
(14)治験薬投与開始から終了7日後までの間に、コンドームを使用することに同意できない患者
(15)遺伝性キサンチン尿症の患者
(16)低尿酸症(1 mg/dL未満)又はキサンチン尿路結石と診断されたことがある患者
(17)痛風の既往又は痛風あるいは高尿酸血症の治療中の患者
(18)免疫抑制剤を服用中の患者
(19)過去に化合物Aの投与を受けた患者
(20)その他、治験責任医師又は治験分担医師が不適格と判断した患者
錠剤A:1錠中に化合物Aとして200mgを含有する(化合物A群に投与)
錠剤B:錠剤Aと概観が同じで化合物Aを含有しない(コントロール群に投与)
剤形:淡黄色フィルムコーティング錠
本試験に使用される錠剤A及び錠剤Bは、国際公開第2010/104170号パンフレットに記載の方法、自体公知の方法又はそれらを適宜組み合わせることによりにより製造する。
4.1 用法・用量
(1)投与量
投与群ごとに、標準治療に加えて以下用量の治験薬を投与する。
[化合物A群]
化合物A1800mg × 2回/日× 1日間+ 800mg × 2回/日× 13日間(最長)
[コントロール群]
化合物Aプラセボ9錠× 2回/日× 1日間+ 4錠× 2回/日× 13日間(最長)
[化合物A群]
錠剤A(化合物A200mgを含有)を、1日目は1回9錠を2回、2日目以降は1回4錠を1日2回、最長13日間、経口投与する。
[コントロール群]
錠剤B(化合物Aを含有しないプラセボ)を、1日目は1回9錠を2回、2日目以降は1回4錠を1日2回、最長13日間、経口投与する。
Day 1は、1回目の治験薬投与から少なくとも4時間以上の間隔を空けて2回目を投与する。
投与期間は最長14日間とする。
5.1 治験実施手順
以下の手順に従って本治験を行う。
(1)選択・除外基準の確認、治験の説明、同意の取得、投与開始前の観察・検査の実施
(2)患者の登録(治験組入れ)
(3)治療への割付け
(4)治験薬の処方、投与開始
(5)所定の観察・検査実施、評価・判定
(6)追跡調査
5.2.1 有効性の評価基準
(1)有効性の判定基準
1) 主要評価項目の判定基準
治験薬投与開始から、体温、SpO2及び胸部画像所見が「軽快」し、その48時間後にSARS-CoV-2が「陰性化」した時点までの時間を、主要評価項目として評価する。
体温、SpO2及び胸部画像所見の「軽快」は、体温、SpO2及び胸部画像所見のすべてが、以下a)~c) の状態に達して2日間以上(48時間以上を目安) 維持した場合と定義する。また、SARS-CoV-2の「陰性化」は、SARS-CoV-2が以下d)の状態に達して12時間以上それを維持した場合と定義する。
a) 体温:37.4°C以下(解熱鎮痛薬の使用後4時間以内の測定値は使用しない)
b) SpO2:96%以上(酸素療法なしの条件下)
c) 胸部画像所見:最悪時からの改善
d) SARS-CoV-2:RT-PCR (定性) 検査で陰性化
a) SARS-CoV-2消失までの時間
治験薬投与開始から、SARS-CoV-2が「陰性化」するまでの時間を、SARS-CoV-2消失までの時間として評価する。
b) 体温、SpO2及び胸部画像所見の各症状・所見別持続時間
体温、SpO2及び胸部画像所見のそれぞれの症状・所見ごとに、治験薬投与開始から、上記1) a)~c)の状態に達して2日間以上(48時間以上を目安) 維持した時点までの時間を、各症状・所見別持続時間として評価する。
c) NEWS分類
治験責任医師又は治験分担医師が記録した臨床症状・所見(意識状態) 及びバイタルサイン(SpO2、体温、血圧、脈拍数、呼吸数) などから、 NEWS分類の各パラメータのスコアを導出し、合計値を算出する。
治験責任医師又は治験分担医師は、治験中に発現した有害事象の程度及び因果関係を判定する。
非重篤な肺炎を有するCOVID-19患者を対象に、肺炎の標準治療に化合物Aを追加した時の治療効果が追加しない場合と比べて上回ることを、主要評価項目及び/又は副次評価項目で検証できる。具体的には、例えば、適切に定義した有効性解析対象集団を対象に試験結果を解析した場合、化合物A群の治療効果がコントロール群を上回っていることが、主要評価項目及び/又は副次評価項目で、統計的に有意に確認できる。
Claims (6)
- 非重篤な肺炎を合併した患者に対して投与される、6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミド又はその塩を有効成分として含有するコロナウイルス感染症治療剤。
- 患者が、新型コロナウイルス感染症患者である、請求項1に記載のコロナウイルス感染症治療剤。
- 患者が、以下(1)~(3)の基準をすべて満たす患者である、請求項1又は2に記載のコロナウイルス感染症治療剤。
(1)コロナウイルス陽性である
(2)胸部画像で肺病変を認める
(3)37.5℃以上の発熱を認める - 6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミドとして、1000~2400mgを1日2回(1日目)、400~1200mgを1日2回(2日目以降)投与される、請求項1~3いずれか1項に記載のコロナウイルス感染症治療剤。
- 6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミドとして、1800mgを1日2回(1日目)、800mgを1日2回(2日目以降)投与される、請求項1~3いずれか1項に記載のコロナウイルス感染症治療剤。
- 6-フルオロ-3-ヒドロキシ-2-ピラジンカルボキサミド又はその塩を14日間投与する、請求項1~5いずれか1項に記載のコロナウイルス感染症治療剤。
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- 2021-03-26 CN CN202180031625.2A patent/CN115884774A/zh active Pending
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US20230127703A1 (en) | 2023-04-27 |
EP4129291A4 (en) | 2024-04-10 |
EP4129291A1 (en) | 2023-02-08 |
AU2021245634A1 (en) | 2022-10-20 |
CN115884774A (zh) | 2023-03-31 |
BR112022019486A2 (pt) | 2022-11-16 |
CA3173148A1 (en) | 2021-10-07 |
TW202203923A (zh) | 2022-02-01 |
JPWO2021200651A1 (ja) | 2021-10-07 |
MX2022012033A (es) | 2022-10-27 |
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